A few years after the events of a solar eclipse, one that foretold the coming of an angel of darkness, a lone swordsman walks into a bar where an elf is being tormented by a group of bandits. When the bandit leader threatens to kill a red-haired youth requesting membership, Guts beats the gang and takes his leave with the freed elf, named Puck, following him. Eventually, Guts reluctantly accepts being picked up by an old priest named Adolf despite warning him that he is constantly hunted by evil spirits. After sunset, waking up after a nightmare, Guts and the wagon are attacked by spiritually-possessed skeletons with Adolf and his daughter Collette killed off during the assault. Guts spent the night fighting the skeletons and then a tree animated by pagan spirits. Despite Puck attempting to console Guts, who hears the spirits' constant taunting, the swordsman scoffs the deaths of Adolf and Collette as proof of their weakness. Guts attempts to leave before he is surrounded by the Holy Iron Chain Knights, who have been tracking him since the day they investigated the events of the solar eclipse and came across the remains of mutilated men in a pool of blood.
Despite his fatigue, Guts easily kills some of the Holy Iron Chain Knights, who have been sent by the Church of the Holy See to capture him. When Guts finds himself overwhelmed by their vice-commander Azan, he attempts a dash at the knights' leader Farnese de Vandimion. But Guts is wounded by a cross arrow bolt, followed by a piece of wood, and falls unconscious. Once stripped of his gear and brought to the knights' camp, Guts is interrogated by Farnese for answers that include the mysterious demise of the Band of the Hawk, having found the mercenary group's bloodied remains after the solar eclipse. As Guts mocks on her authority and her faith, Farnese whips him until Azan arrives. Guts is placed in a cage soon after, freed by Puck at nightfall as the spirits start to awaken. Guts enters Farnese's tent to recover his equipment while finding her in the middle of self-flagellation, deciding to take her hostage for a quick escape. The other knights work to cease the fire Guts started while Serpico gives chase after the swordsman, the knight finding himself surrounded by pursing spirits.
The spirits pass Serpico and chase Guts to an abandoned mansion as he tells Farnese, who is unable to see them or Puck, that they are her god's "miracles". Guts quickly gets Farnese and the horse inside as the spirits possess hounds and use them to break in. Guts manages to kill the dogs before facing the estate's kennel master: an Apostle who mounted the remains of the woman he cared for and unknowingly sacrificed on the foyer. Guts defeats the Apostle and kills him after attempting to interrogate him on the God Hand, searching for Farnese after she fled in terror. Guts finds Farnese as she was about to violated by the possessed horse, killing the creature as its act brought back horrible memories. Farnese then ends up being possessed herself and forced to act her lust before sun rise. Serpico retrieves a mortified Farnese and escorts her back to their camp while allowing Guts a reprieve. Meanwhile, in the city of Windham, the King of Midland passes away after a vision of Griffith returning while a foreign army comes to his land.
After having a vision of Casca being burned at the stake, Guts returns to Godo's hut to check in on her. After he arrives, he receives the terrible news of Casca's disappearance. Guts struggles with his past demons along with the growing evil within his soul as he fears Casca is the only remainder of his sanity left. After talking with Rickert at the Hill of Swords, Guts resolves himself. Godo arms Guts with new armor and a reforged Dragonslayer to prepare him for his new journey. Meanwhile, the Holy Iron Chain Knights accompany the Grand Inquisitor's caravan as an escort. They are soon attacked by rebels who seek revenge against the Holy See, but are swiftly captured by masked inquisitors. The Grand Inquisitor himself, Mozgus, steps outside to lecture the rebels before having the survivors executed on breaking wheels. Unbeknownst to everyone, Casca is cluelessly traveling with the Holy Iron Chain Knights.
Guts encounters and kills a party of Kushan scouts, saving the life of Isidro who follows him out of admiration. Meanwhile, catching some starving refugees attacking a food wagon, Mozgus brings a refugee and her baby to the abbey; although her baby is cared for, Mozgus tortures her for her blasphemy. In the refugee's camp, Luca keeps Casca disguised as her bandaged sister "Elaine" and shares her payment from clients including the knight Jerome with her fellow prostitutes. One of them, Nina, worries about her disease while fetching water with Casca, not noticing the spirits stalking them. Isidro catches up with Guts, when they are attacked by more possessed corpses.
As Casca is saved by the monstrous fetus, Guts encounters the mysterious Skull Knight for the first time in years since the Eclipse. Guts is disturbed to learn that the God Hand are using St. Albion as the site of a horrific ritual to restore Griffith's corporeal form, refusing to accept it as fate as he resumes his run towards the city with Isidro still following. The next day, as Farnese finds herself struggling with her faith, Nina meets her reoccurring customer Joachim and tests his love for her by having him come with her to a midnight orgy held by the pagan cult's goat-headed leader. Joachim gradually engages until learning that the pagans are cannibals and runs off before he was seemingly killed. Nina breaks down before seeing Luca, who disciplines her before forgiving her and then learning that Casca followed her. Casca nearly gets raped by the pagans who found her until they were possessed by spirits. Luckily, Casca was saved by the fetus and the surviving pagans assume she is a witch.
Returning to camp while fearing persecution, Luca finds Pepe arrested by pagan hunters and tries to defend her before they are saved by Guts, who just arrived to St. Albion and dispatched the hunters while asking for Casca's whereabouts. Luca takes Guts to Casca's tent upon noticing his brand, only to find that a fearful Nina abducted her. But Isidro finds Nina as she and Casca are captured by the pagan cult, who intend to marry the "Black Witch" to the Great Goat while Nina is be to sacrificed. After the Holy Iron Chain Knights are led to the pagans' cave by Joachim, Farnese finds herself in another unnatural situation when they are attacked possessed cultists who slaughtered their own. During the ensuing chaos, as Isidro attempts to save Casca, the Great Goat is transformed into a satyr-like Apostle by a mysterious observer and kills anyone within reach. When the Great Goat then attempts to consummate his marriage, Guts arrives at the last second to save Casca as the two see each for the first time in two years.
Having arrived just in time, Guts saves Casca as the two are reunited. However the reunion is cut short once the Great Goat attacks Guts. Guts battles the fearsome Apostle as the Holy Iron Chain Knights retreat with Isidro, Puck and Nina escaping with Casca. Guts succeeds in killing the Great Goat with the help of Rickert's miniature bombs while Casca and Nina are once again confronted by the Holy Iron Chain Knights, who capture them. Guts makes his way out of the cult's cavern only to be ambushed by Serpico on a cliff side. Serpico reveals he has been seeking to kill the Black Swordsman and has prepared the duel in his favor due to the terrain and Guts' current state. Guts is surprised by Serpico's remarkable speed and agility but manages to win the encounter once he crushes Serpico's sword with his iron prosthetic. Serpico escapes by using Guts' miniature bombs against him while Guts confronts Isidro about Casca's disappearance. Guts, Isidro and Nina return to the Tower of Conviction while Puck searches the cells inside for the duo. Nina is taken first by Mozgus' disciples to be tortured first for information on the "Black Witch", leaving Casca behind. All the while, a mysterious egg-shaped Apostle dwells at the top of the Tower; waiting for its plan to come to fruition.
After Nina named her as the witch he seeks, Mozgus places Casca in an iron maiden upon seeing her brand. But it causes the spirits of the tortured to manifest as a flesh-eating blob of blood with almost everyone able to escape. While Luca and Isidro use Jerome to free Nina, Guts forces Farnese to take him to the torture chamber where Puck tells him Casca is still alive. With Casca trapped inside it, the blood moves up the tower as Mozgus' group barricade themselves in the chapel. But they are then transformed by the observer, Mozgus deeming it divine providence as he burns away some of the blood with his flames. Though he freed Casca and saved Luca's group, Mozgus intends to have the former burned at the stake while his men attack the latter. Luca sacrifices herself so Jerome can save Nina, only to be saved by the Skull Knight as he was about to attack the observer. Guts arrives soon after and battles three of Mozgus' men as the inquisitor's group all sprout wings.
Luca is spirited away by the mysterious observer, who reveals himself to her as a Behelit-like Apostle self-dubbed the Egg of the Perfect World. The Egg tells Luca his story and his long observation of everyone in St. Albion, detailing his ideals and the event to soon occur before fleeing from the Skull Knight. The Skull Knight takes Luca to safety as the living mounds of starved corpses rise up. Back in the Tower of Conviction, while the other disciples deal with Guts, Mozgus and the Twins fly off with Casca. While Guts manages to kill Mozgus's disciples, the possessed blood causes the tower to partially collapse with Guts enduring the cave-in to see the chaos unfolding in the slums. Mozgus uses his powers to keep the corpses at bay while the refugees proceed to build a pyre to burn Casca on. Guts sees this while noticing the four senior members of the God Hand manifesting through the blood.
As Luca walks back to St. Albion after the Skull Knight took her to the outskirts, the Egg of the Perfect World swallows the dying Demon Child out of sympathy before resuming his climb up the Tower of Conviction. At the same time, enlisting Jerome and Nina's help, Isidro uses a makeshift pulley system to free Casca as she was about to be burned alive. Mozgus nearly catches them after forming a barrier to keep the corpse mounds at bay when Guts leaps off the tower and impales the inquisitor. But Mozgus's bible shielded him from the attack while he fully transforms. As Isidro's group eliminate the last of Mozgus's disciples, the inquisitor's flame barrier dies out as he attempts to give Guts a chance to recant. But Guts instead uses his miniature bombs to blow apart the unprotected chink in Mozgus' armored body to land the death blow. After a brief reunion with Casca, the corpses manage to flood into St. Albion as Guts gives his group torches so they can outlast the few remaining hours of night.
Guts and his group fend off the flood of corpses with their fire while Luca saves Nina down below the tower. Meanwhile, the Egg of the Perfect World collects the energy of St. Albion's souls and sacrifices himself to resurrect Griffith in a corporeal form. The Tower of Conviction collapses, killing everyone inside as the sun rises. Guts and the others collect themselves, but are quickly surrounded by Silat and his Kushans. The Kushans are immediately repelled by Nosferatu Zodd who bursts through the rubble and marches to a nearby hill. At that moment, everybody ceases fighting to witness Griffith arising from the ground as Zodd kneels before him. Guts goes to immediately attack, but is stopped by Casca. As the Kushan army proceeds with its invasion, Zodd and Griffith escape into the skies while Guts, Puck and Casca ride to Godo's on horseback. Isidro departs on his own while Luca mourns the death of the Egg. While Nina reunites with Joachim, Farnese leaves her faith behind; deciding to follow Guts as Serpico travels with her.