The story started long back in ancient time, a war between the underworld and the human world was taking place. The battle between dark and light was ended by a rebelling demon, who rose against the demon king Mundus. He was known as Sparda or the Legendary Dark Knight. He seals the gate between two worlds in a ritual, building a tower named Temen-ni-gru.
The seal was done using the blood of his own and a priestess, placing it in his sword to ensure its strength. He used two perfect amulets, which was the key to enter the demonic world to keep the seal secure. He then disappeared suddenly and was remembered as a legend. Sparda once again appeared in the 20th Century and married Eva, they conceive and had two twins Dante and Vergil. Sparda gives the amulet to Eva as a gift and disappears to the unrevealed circumstances, keeping his wife and sons alone. As the boys grow, Eva gives two of them equal halves of the Perfect Amulet. Not much later, Mundus plans revenge on Sparda's family and send demons to kill his family which resulted in Eva's death. Dante escapes, thinking his brother Vergil to be dead as well.
Later on, now an adult Dante opens a shop working like a devil hunter, hunting demons and saving others for bounty, using a sword his father left for him, "REBELLION". In his journey, he meets Nell Goldstein, who owns a gunshop and before dying gives Dante a semi-automatic pistol, Ebony and Ivory.
On the other hand, Vergil being alive tries to find more about his father and meets Arkham, who sacrificed his wife to gain demonic strength, which left him with scars and a revengeful daughter Mary. Arkham tells everything to Vergil and says to get the other half of the amulet from his brother Dante.
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Meanwhile, Dante's amulet was stolen by a girl Alice from his shop. Dante sees her and follows her to a church, where he meets his brother and soon after they talk, both of them realize that both have different paths and end up in a fight in which Dante loses and Vergil take the other half of the amulet; seeing Dante begging for the amulet, he returns it saying, he can take it anytime he wants to.
After a year of the reunion with his brother, Arkham arrives and gives Dante invitation from Vergil, before disappearing. Soon after that, Temen-ni-gru appears and Dante thoughts it as the invitation from his brother and climbs to the tower by defeating the gatekeeper. Inside the tower, he meets Jester, a mysterious demon who helps Dante to climb the tower by telling about the tower's layout. Dante had an encounter with Mary there, who couldn't kill her father. Dante then advances to the top and meets Vergil and was overpowered by Vergil.
Vergil kills Dante with his katana "Yamato" and takes the amulet, to ensure his kill, Vergil stabs Dante with his own sword "Rebellion" but tasting Dante's blood Rebellion now harnesses the devil trigger power in him. He after gaining consciousness follows Vergil and Arkham and was stopped by Mary, the two meet formally and get to know each other and asks her to abandon his old name and names her as "Lady".
Before entering the control room of the tower, Vergil stabs Arkham stating him unuseful for him. Meanwhile, Dante and Lady reach and find Arkham to be dead, seeing this Dante leaves Lady with Arkham's dead body, as soon as he leaves Arkham awakens for a while and tells Mary about himself being manipulated by Vergil from the starting, hearing this Lady transfers her vengeance to Vergil.
On the other hand, Vergil reaches the main seal and gets enraged as the doesn't open, he rushes to kill Dante and take his blood which he thinks is the final key to the seal, Mary interrupts both and asks them to stop. Meanwhile, Jester comes congratulates three of them to be a part of the plan, soon it was revealed Jester is Arkham himself, who didn't fully fail in his ritual to become a demon. He then reveals the final ingredient to the ritual as the blood of a priestess and stabs his daughter in legs, as soon the blood seeps to the seal, the tower opens and gate gets unlocked. Inside Arkham was able to find the sword of Sparda, "The force edge" and masquerades Sparda. Dante and Nero fight with Arkham and defeats him, he loses the Force edge and the amulet and eventually falls to the ground. He pleads for his life to Mary, but she waves her final goodbye saying, her name was Lady and shots him to death.
Back in demon world Dante and Vergil regain their amulets and fight for their father's sword, Vergil was defeated by Dante and falls in the darkness, making a cut on Dante's hand which he took as a sign from his brother not to follow him to the darkness. Later he returns to the human world, sealing the gate behind. Lady notices tears on Dante's eyes due to loss of his brother, she claims, somewhere a DEVIL MAY CRY, which later turned out to be the new name for Dante's shop. On the other hand, weak Vergil fights Mundus and gets defeated, taking this chance Mundus corrupts him.
A few years later, a mysterious lady appears and involve in a fight with Dante, who defeats her later she introduces herself as Trish and that was just a mere test of his abilities. She informs him Mundus is planning a return and as soon as Trish opens her glasses, Dante finds a striking resemblance to his mother. Trish takes him to the island and leaves Dante behind to explore the island, Dante fights many demons and meets with the demon "Nelo Angelo".
Dante thrice had encounters with him as he advanced the tower, later in the fight he comes to know he is corrupted form of his brother Vergil. Dante defeats his brother and gets the other half of the amulet which made him unleash the full power of Sparda in the force edge. Later, he finds Trish injured inside the cave, as he advances to help her, one of Mundus's demon ambushes him. As soon as Dante defeats the demon, Trish reveals that she was working for Mundus, the whole time. The after effects of the fight caused a rock to fall on Trish from which Dante saves her. Being asked by Trish the reason to save her, he tells her about the resemblance of her with his mother.
Finally reaching to fight Mundus, Dante finds out he is preparing to kill Trish on her failure to trap and kill Dante. He advances to save Trish but was shot down by Mundus, seeing this Trish frees herself from shackles and takes the final blow on herself and dies. Mundus and Dante then go to another plane of existence and there Mundus offers him his mother. Dante gets enraged and takes the form of Sparda and defeats and seals in a temple. He leaves the Force edge and amulet near the body of Trish and was again attacked by Mundus on his way out. As he was ready to take a blow on Dante, Trish appears and lends her power to Dante. Both then seal Mundus back in the demon world again. As soon as the fight ends, Trish apologizes to Dante and weeps, which meant she isn't a devil anymore, as devils never cry.
Later, in the story, we meet Nero, who has a resemblance to Dante and Vergil. He works for "The Order" and is seen to rush to church, fighting demons and still reaches on time before his childhood love's performance. He gives her a gift and as the ceremony advances, Nero's right starts to glow and then enters Dante and kills Sanctus, the head of the high order. Dante kills other members of "The Order" and as soon he reaches to kill Kyudiay's brother Kratos. Nero brings out his devil bringer arm and impales Dante with his own sword against the statue of Sparda. Dante revealed knights of "The Order" to Nero as the demons. Dante leaves the place and Kratos summons Nero to bring him back to "The Order". As the three gets out from the church, they see the city being attacked by other demons, Nero rushes to fight with them. As the story advances, we get to know about Agnes who work with Kratos to bring back Sanctus to life and a huge giant named Saviour which is operated by Sanctus after coming back to life, the story has an emotional curve when Sanctus takes Nero inside into the Saviour. Dante comes to rescue and saves the day, a major role is played by Gloria or Trish, who infiltrated "The Order". At the end of the story, Dante hands over Vergil to Nero and says "it should be in the family." The game ends with Nero kissing his childhood love and shooting some demons.
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