On June 26, 2008, Mayo was selected 3rd overall in the 2008 NBA draft by the Timberwolves.
Later that day, he was traded to the Memphis Grizzlies, along with Marko Jarić, Antoine Walker, and Greg Buckner, swapping them for the 5th overall pick Kevin Love, Mike Miller, Brian Cardinal, and Jason Collins.
Mayo was a part of the Select Team that helped get the U.S. national team ready for the 2008 Summer Olympics in Beijing.
In his NBA Summer League debut, Mayo had 15 points to lead the Grizzlies to an 88–75 win over the New Orleans Hornets.
During his rookie season, Mayo scored 30 or more points seven times.
Mayo was the runner-up for the 2008–09  NBA Rookie of the Year Award, finishing second behind Chicago Bulls point guard Derrick Rose.

In his sophomore season, on November 1, 2009, Mayo scored a career high 40 points against the Denver Nuggets on 17 of 25 shooting.

Mayo was late for a game-day shootaround and was taken out of the starting lineup starting November 20, 2010.
On a return flight to Memphis from Los Angeles, Mayo was involved in a fight with teammate Tony Allen over a debt from an in-flight card game.
On January 27, the NBA suspended Mayo for 10 games following a positive test for the steroid  dehydroepiandrosterone (DHEA), which violates the league's anti-drug program.
Mayo blamed an over the counter supplement that he didn't know was banned by the NBA for the positive test, but he declined to say which supplement he used.
He later said an unnamed energy drink he bought at a gas station contained the banned substance.

Despite playing in all 66 games of the shortened 2011–12 season, Mayo did not start in any games for the Grizzlies, playing as a sixth man.
When he was asked if being a reserve hurt his value, he answered: "I would say so, I would probably say so.
What do you think?"
On June 26, 2008, Mayo was selected 3rd overall in the 2008 NBA draft by the Timberwolves. Later that day, he was traded to the Memphis Grizzlies, along with Marko Jarić, Antoine Walker, and Greg Buckner, swapping them for the 5th overall pick Kevin Love, Mike Miller, Brian Cardinal, and Jason Collins. Mayo was a part of the Select Team that helped get the U.S. national team ready for the 2008 Summer Olympics in Beijing. In his NBA Summer League debut, Mayo had 15 points to lead the Grizzlies to an 88–75 win over the New Orleans Hornets. During his rookie season, Mayo scored 30 or more points seven times. Mayo was the runner-up for the 2008–09  NBA Rookie of the Year Award, finishing second behind Chicago Bulls point guard Derrick Rose.
In his sophomore season, on November 1, 2009, Mayo scored a career high 40 points against the Denver Nuggets on 17 of 25 shooting.
Mayo was late for a game-day shootaround and was taken out of the starting lineup starting November 20, 2010. On a return flight to Memphis from Los Angeles, Mayo was involved in a fight with teammate Tony Allen over a debt from an in-flight card game. On January 27, the NBA suspended Mayo for 10 games following a positive test for the steroid  dehydroepiandrosterone (DHEA), which violates the league's anti-drug program. Mayo blamed an over the counter supplement that he didn't know was banned by the NBA for the positive test, but he declined to say which supplement he used. He later said an unnamed energy drink he bought at a gas station contained the banned substance. 
Despite playing in all 66 games of the shortened 2011–12 season, Mayo did not start in any games for the Grizzlies, playing as a sixth man. When he was asked if being a reserve hurt his value, he answered: "I would say so, I would probably say so. What do you think?"
O. J. Mayo