Mendenhall revealed his decision in an article, saying, "Football was pretty cool, but I don't want to play anymore."
At age 26, Mendenhall will call it quits after one season with the Arizona Cardinals and five with the Pittsburgh Steelers. He was twice a 1,000-yard rusher and appeared in two Super Bowls with Pittsburgh.
Mendenhall ran for just 687 yards with a 3.2-yard average and eight touchdowns in 15 games last season. He played just six games during an injury-filled 2012 with Pittsburgh before signing as a free agent with the Cardinals last March.
"I've really enjoyed my time in the NFL and have had tons of fun," Mendenhall wrote. "I feel like I've done it all.
The Steelers selected the Illinois product with a 23rd overall pick in the 2008 NFL Draft. He ran for 1,108 yards in 2009 and finished with 1,273 yards the following year.
Mendenhall finished his career with 4,236 yards and 37 touchdowns on the ground, adding 95 catches for 795 yards with two scores.