This game offers the only visual explanation of how Dante's sword Rebellion remains on his back without being fastened to his clothes. (His abilities allow him to "summon" the sword at will through the Angel markings on his back.)
Unlike previous DMC installments, Dante and Vergil do not transform into demonic "creatures" when their devil triggers are activated. They remain in human form and their powers are portrayed by a change in their hair color, eye color, skin color, and clothing.
In the story for the original games, Virgil was the older of the twins, where in this game Dante is the senior brother.
Dante primarily wields his sword rebellion with his left hand, unlike previous installments of DMC where he used his right hand.
The three scar-like marks on Mundus' forehead are an inverted representation of his three-eyed demon form. (As seen in previous games) During the fight with Lilith, it can be seen that Mundus' spawn also has three eyes.
In the previous DMC installments, Dante and Virgil were Half Demon/Half Human. Here in DmC, they are Nephilum- Half Demon/Half Angel.
This is the first installment of Devil May Cry where Dante is not the proprietor of a shop by the same name.
Aside from Lilith who is killed by Vergil, Phineas is the only Demon Dante encounters that he doesn't kill.
The demon Phineas, is a possible caricature play on the real life Phineas Gage; the infamous railroad foreman who survived a railroad spike being driven through his skill. The deformation of Phineas the demon's skull, resembles the damage done to Gage. There was also significant change to Gage's personality and behavior due to the warping of his frontal lobe. (In certain mythologies, the Brain's frontal lobe is believed to be responsible for possible "Clairvoyance", which could account for demon Phineas' visions of the future.)
At the beginning of the game, a wig flies onto Dante's head making him look like the his old rendition in previous games, to which he replies "Not in a million years."
Including the first installment Devil May Cry, this game is one of two out of the five DMC/DmC games that does not include a human villain who is attempting to become a demon.
In the previous DMC installments, as a Half Demon/Half Human hybrid, Dante ages like a human and could possibly die of old age. In this DmC however, as Nephilim he may be immortal due to both parents being immortal.
In previous games, Vergil lived by the sword and had reserves about using guns; only yielding them on one occasion when he and Dante defeated Arkham. In DmC, Vergil does not share such reserves as he freely used an automatic weapon to kill Lilith, her child and fend off Mundus' soldiers.
Just before Kat shows up at Dante's trailer, he heals himself of scratches by willing his healing factor. This aspect of his powers differs from the previous installments, where his demonic powers allowed him to heal automatically (almost instantly) without willful promoting.
The 3 unique scars on Mundus' forehead, pay homage to the original Devil May Cry series; in which Mundus would appear out of body in the form of three glowing red power spheres.
After fighting and killing the Succubus, Dante receives a pair of fiery Gautlets, much like the kind a previous Dante receives in DMC1. DMC 2 is the only game without some sort of gautlets.