First, lure the boss into destroying the food carts around the room. This will create more space in which to fight. You can evade the monster's charge easily (it will crouch before attacking) while its ground slam can be prevented by shooting its vulnerable flesh (if you get knocked down, rapidly press the button that matches the one on the screen to stand up quickly). Inflicting enough damage will cause the boss to collapse, allowing you to fire at its head. The explosive canisters can also be used to stun it. Sniper rifles are good for attacking it from a distance, though machine guns are also very effective. There is plenty of ammo around the chamber and also an herb, so don't worry about getting low on supplies.
It can be scanned multiple times by the Genesis scanner allowing players an assured herb.
The Draghignazzo also appears as a boss in Raid Mode, though it is noticeably weaker than the version fought in the main storyline. There is also a smaller version known as a "Baby Draghignazzo" that is virtually identical to its "parent", though it is even shorter than a human.