The designation opens the door for rookie Wayne Gallman to make his first career start.
Perkins injured his ribs last week against the Tampa Bay Buccaneers. Gallman filled in after the injury and carried the ball 11 times for 42 yards and added a 4-yard touchdown reception.
After four games, Perkins has just 61 rushing yards on a paltry 1.9 yards per carry. Backups Orleans Darkwa and Shane Vereen have been equally as ineffective for the second-worst rushing attack in the league.
Center Weston Richburg has also been ruled out due to a head injury. The Giants and Chargers both hope to record their first victory of the season on Sunday.