Mendenhall, the team's top draft pick, has a fractured shoulder, while Simmons has an Achilles tendon injury. Both players will be placed on injured reserve.
Jeff Reed's 46-yard field goal with 9:01 remaining in the extra period gave the Steelers a hard-fought 23-20 victory over the Ravens in one of the most memorable games between the two AFC North rivals.
Reed's game-winner – the seventh of his career – was set up by a 21-yard catch-and-run by reserve running back Mewelde Moore on third down from midfield.
Baltimore won the coin toss to open the overtime, but second-year linebacker Lawrence Timmons' first career sack on third down forced the Ravens to punt from their 12-yard line.
Pittsburgh took over from its 43 following the punt and Moore's catch set up the game-winner.
The victory moves the Steelers (3-1) into first place in the AFC North Division, a half-game ahead of the Ravens (2-1).
Baltimore outgained the Steelers 146-46 in total yards in the first half when the Ravens built a 13-3 lead on a pair of Matt Stover field goals and a four-yard touchdown pass by rookie quarterback Joe Flacco to tight end Daniel Wilcox late in the second quarter.
The Steelers opened with a strong drive on their first possession, taking over at their 24 and moving to the Baltimore 20 before settling for a 49-yard Reed field goal and a 3-0 lead.
Baltimore scored 13 unanswered points to take the 13-3 lead into the half and maintained it throughout much of the third quarter as the Steelers failed to get a first down after their opening possession.
Quarterback Ben Roethlisberger gave a speech at halftime, imploring his teammates to play better.
But things didn't get any better in the second half until a costly personal foul by Baltimore linebacker Jarrett Johnson after an end-around by Nate Washington ignited the Pittsburgh offense.
The 15-yard penalty gave the Steelers only their second first down since the opening drive. It also moved the ball into Baltimore territory and Pittsburgh went to a no-huddle offense.
Three plays later, Roethlisberger, who was 14 of 24 for 191 yards, one touchdown and one interception, recognized a Baltimore blitz and threw to wide receiver Santonio Holmes on a slant route. Holmes caught the ball 15 yards downfield and made defensive backs Chris McAlister and Ed Reed miss en route to a 38-yard touchdown.
James Harrison then sacked Flacco on the first play of Baltimore's ensuing possession – Harrison's second sack of the game – and LaMarr Woodley scooped up a fumble at the Baltimore 5 and rambled into the end zone. The score gave the Steelers 14 points in 15 seconds and a 17-13 lead.
The Steelers added Reed field goal, this one from 19 yards, with 9:19 remaining to take a 20-13 lead. Pittsburgh got the ball to the Baltimore 1 – with Hines Ward picking up 49 yards on a reception – but Moore was stopped on a third-down run, forcing the field-goal attempt.
Failing to get into the end zone would prove costly. Baltimore tied the game with 4:02 remaining on a two-yard touchdown run by fullback Le'Ron McClain to tie the score at 20-20.
Steelers linebacker Andre Frazier was injured covering the game's opening kickoff. He was hit by Baltimore's Haruki Nakamura in what appeared to be helmet-to-helmet contact. Frazier suffered what was called a spinal injury and was taken off the field on a backboard. He appeared to have movement of his extremities and was walking around the team's locker room following the game.