Charles's 2011 season was short lived. In a Week 1 loss to the Buffalo Bills, Charles rushed for 56 yards on 10 carries and had a receiving touchdown. The following week, against the Detroit Lions, Charles ran for 27 yards on two carries, before suffering an ACL injury. Chiefs head coach Todd Haley confirmed the next day that Charles would miss the remainder of the 2011 season. Charles was officially placed on injured reserve on September 19.
Coming off of an ACL injury in 2011, Charles had an All-Pro caliber season, running for 1,509 yards and five touchdowns. Once again, Charles proved to be very efficient running the ball as he managed a 5.3 yard per carry average on the year. In the season opening 40–24 loss to the Atlanta Falcons, he had 87 rushing yards on 16 carries in his first action back from injury. In Week 3 against the New Orleans Saints, Charles ran a career-high 33 times for 233 rushing yards, scored a rushing touchdown, and caught six passes for 55 yards to earn his first AFC Offensive Player of the Week nod. Charles became the first player in franchise history to rush for at least 200 rushing yards and have at least 50 receiving yards in the same game. His 91-yard rushing touchdown in the third quarter was the longest rushing play in franchise history, a feat later tied by Damien Williams in the 2019 season. In Week 5 against Baltimore Ravens, Charles had 31 carries for 140 rushing yards in the 9–6 loss. However, in Week 8, Charles carried the ball only five times for four rushing yards in a 26–16 loss to the Oakland Raiders. When asked the reason why, head coach Romeo Crennel said "Now, that I'm not exactly sure, either." In Week 10, against the Pittsburgh Steelers, he had 23 carries for 100 rushing yards in the 16–13 loss. On November 25, in Week 12 against the Denver Broncos, he had 23 carries for 107 yards in the 17–9 loss. In a 30–7 loss to the Cleveland Browns later in the season, Charles carried the ball 18 times for 165 rushing yards and a rushing touchdown. On December 2, against the Carolina Panthers, he had 27 carries for 127 rushing yards in the 27–21 victory. In a 20–13 loss to the Indianapolis Colts, Charles carried the ball 22 times for 226 rushing yards and a rushing touchdown. He became the second player in franchise history, joining Larry Johnson, to record two games with at least 200 rushing yards in a single season. Charles's performance was his second career game with over 200 rushing yards while averaging more than ten yards a carry. He became only the second player in NFL history to accomplish the feat, after Adrian Peterson, who accomplished his feat in the 2012 season as well. Charles carried the ball at least 20 times in six games, and in each of those games managed at least 100 yards. This has been a trend throughout his entire career, in every game he has carried the ball 20 times, he has gained at least 100 yards. On December 23, 2012, following his qualifying 750th career carry, Charles broke NFL legend Jim Brown's 47-year-old all-time average yards per carry record of 5.22 with an average of 5.82. He was named to his second Pro Bowl as a result of his successful season. On the NFL Top 100 Players of 2013, he was ranked 20th by his peers.