Sepulveda tore the anterior cruciate ligament in his right knee while trying to make a tackle, the Pittsburgh Tribune-Review reported.
The injury occurred in the second quarter during Lardarius Webb's 35-yard punt return. Sepulveda stayed in the game to hold for field goal and extra point tries by Shaun Suisham, who also punted the rest of the way.
Sepulveda hurt the same leg during training camp in 2008.
His injury was not the only one to trouble the Steelers Sunday.
Tight end Heath Miller was knocked out of the game with a concussion and right tackle Flozell Adams suffered a high ankle sprain.
"We'll put the healthy men on the field next week and move forward," Coach Mike Tomlin said after the Steelers improved to 9-3.