The melee attack is the most basic of all attacks. It can only be performed at close range, and while not holding a gun. Performing a melee attack causes the player to jump forward towards the target, instantly killing him and taking his weapon. It is possible to beat the Prototype using only melee attacks.

In the Beta Release, enemies can no longer be killed instantly with a single punch. Whenever an enemy is punched, they will play a stunned/hurt animation and take a second or two to recover, dropping anything they are carrying in the process. After being hit once and while still in their stunned state, the Player can simply punch the enemy again to kill them. An enemy, however, will not die if they recovered from their stunned state before the player could punch them again.

Stunned enemies can be killed by throwing objects/weapons at them.

In the full version of the game, it takes three hits to kill an enemy and five throwables. However, there are occasionally "criticals", which seem to be random. There is also the fact that if you throw something at an enemy, and then punch them twice, they will die. There is another type of melee takedown that only happens when you land on an enemy. This is a one-hit takedown and can be used much faster. However, it speeds up time as if you had clicked.