Maybe an ancient and powerful mafia clan that has been in hiding for centuries suddenly resurfaces in the Highschool DxD world. Their leader is a very traditional and strict figure who believes in the old ways of the mafia. He sees the devils, angels, and other factions as threats to his clan's way of life and decides to wage war against them. He is a formidable opponent because of his vast experience and the unique and powerful abilities his clan has developed over the years.
It could be a corrupted member of the mafia who has made a deal with a rogue group of fallen angels. This person betrays his own mafia family and works with the fallen angels to create chaos in the Highschool DxD universe. He is very sly and manipulative, always staying one step ahead of the heroes. For instance, he uses his knowledge of the mafia's operations and the power of the fallen angels to set traps for the protagonists.
Maybe a rogue ninja from Gaara's world who somehow follows him into the DxD highschool. This ninja could have a vendetta against Gaara and use the chaos of the DxD world to try and take him down. They could also team up with some of the devils who dislike Gaara's presence to create more trouble for him.
Maybe a rogue Devil who wants to use Ichigo's power for his own gain. He could try to manipulate Ichigo into fighting against the other factions, like the Angels and the Devils who are trying to maintain the balance in the world. This Devil would be very cunning and would constantly be devising new ways to control Ichigo.
It could be a rogue fallen angel who is jealous of the godlike SI's power. This fallen angel might see the SI as a threat to their own plans of ruling the underworld or causing chaos between the three factions in the High School DxD world.
A powerful and corrupted brave saint could be the main antagonist. This character may have been corrupted by the allure of power or some dark magic. She believes that the brave saints should be the supreme rulers and decides to start a war against both the devils and the angels. She uses her knowledge of the brave saint techniques and her own new - found dark powers to cause mayhem and tries to eliminate anyone who stands in her way.
Maybe an ancient entity that was sealed away long ago and is now awakened by the presence of the warrior of creation. This entity could be jealous of the new power in the world and see the warrior as a threat to its own plans of domination, thus becoming the main antagonist.
It could be an envious student who also discovers the 'gamer' aspect but uses it for evil. He might try to undermine the protagonist at every turn, seeing him as a threat to his own power - hungry goals.
It could be a powerful devil who doesn't like the idea of an outsider like Naruto in their world. This devil might see Naruto as a threat to the power balance and wants to eliminate him before he can form strong alliances. He could be a high - ranking noble devil who has his own dark plans for the DxD world and Naruto's presence is ruining it.
It could be an old enemy of Issei's that he never fully defeated. This enemy, having bided their time, finally manages to kill Issei. They could be a powerful devil from a rival faction who saw Issei as a threat to their power and plans.
It could be a powerful devil who wants to take over the entire world now that there is no God to oppose them.
A rogue devil lord who has his own twisted sense of justice. He sees the current state of the devil world in Highschool DxD as weak and wants to reshape it according to his own ideals. The killer then becomes an obstacle in his path as he tries to carry out his plans, which often involve sacrificing the innocent. This antagonist would bring in a moral dilemma for the characters.