Roethlisberger was 26-of-33 passing and Mendenhall ran for 165 yards on 29 carries for the Steelers (2-2), who stopped a two-game losing streak.
The Steelers also scored a touchdown on a pass to Heath Miller by running back Mewelde Moore, who also caught a TD pass. Miller caught eight passes for 70 yards and two TDs and Hines Ward picked up 113 yards on eight catches for the Steelers.
Philip Rivers went 21-of-36 passing for 254 yards and three touchdowns for the Chargers (2-2). Antonio Gates had nine catches for 124 yards and two touchdowns.
The Chargers trailed 28-0 in the third quarters but staged a comeback that fell short in the closing minutes, when the Steelers took over and caped the scoring with a 46-yard field goal by Jeff Reed with 43 seconds remaining on the clock.