Nix began the 2008 season as the Colorado Rockies starting second baseman but over the next month, he saw his playing time diminish. On April 26, 2008, Nix was designated for assignment. He had played in 17 games and batted.111 with no home runs. On April 30 he cleared waivers and was sent outright to Triple-A. in 2011. Nix was batting.300 with 17 home runs and 49 RBI for the Sky Sox in 2008 when his minor league season ended as a result of his being selected for the 2008 USA Olympic Baseball Team. In the team's third game at the Olympics, against Cuba, Nix hit a solo home run in the eighth inning. While leading off the eleventh inning with runners on first and second as per Olympic rules, Nix fouled a ball off his left eye. He left the game for the hospital and missed the rest of the Beijing Games. Team USA lost, 5–4, to the defending champions in eleven innings.
On October 28, 2008, Nix signed as a free agent with the Chicago White Sox. On May 7, 2009, Nix hit his 1st career home run off of Armando Galarraga. He followed with his second career home run just five days later. On May 26, Nix homered twice against the Los Angeles Angels of Anaheim. On the same day, his brother, Laynce homered against the Houston Astros. On May 30, 2010 Nix hit his first career grand slam against the Tampa Bay Rays. On June 18, 2010, he was designated for assignment to make room for prospect infielder Dayán Viciedo.
Cleveland Indians
On June 24, 2010, Nix was claimed off waivers by the Cleveland Indians, and the team designated Shane Lindsay for assignment to make room for him. Jensen Lewis and Luis Valbuena were sent down to Triple A Columbus.
Toronto Blue Jays
On March 29, 2011, Nix was traded to the Toronto Blue Jays for future cash considerations. He made his debut on April 2 against the Minnesota Twins, hitting a home run. On April 22 Nix was slid into by Rays second baseman Sean Rodriguez and left the game with a left leg injury. He was placed on the 15-day disabled list for a left leg contusion on April 23. He returned from the disabled list on May 18, playing against the Tampa Bay Rays. He was designated for assignment on July 2. He became a free agent at season's end.
Nix signed a minor league contract with the New York Yankees on November 23, 2011. He also received an invitation to spring training. Nix was called up on May 3, 2012 by the Yankees. Nix filled in as a backup infielder for the Yankees and started several games at shortstop and third base filling in for Derek Jeter and Alex Rodriguez. Nix was the final out of the 2012 American League Championship Series popping up to first baseman Prince Fielder as the Yankees were swept and eliminated by the Detroit Tigers in 4 games. Nix was placed on the 15-day disabled list on July 3, 2013, due to a hamstring strain. On August 21, Nix was hit by an R.A. Dickey knuckleball and immediately removed from the game with what was later determined to be a broken left hand. On August 22, Nix was placed on the 15-day disabled list. On September 1, 2013 he was transferred to the 60-day disabled list. After the season, Nix was non-tendered by the Yankees, making him a free agent.
Philadelphia Phillies
On January 9, 2014, Nix signed a minor league deal with the Tampa Bay Rays. He was traded to the Philadelphia Phillies for cash considerations on March 28, 2014. He was outrighted to the Lehigh Valley IronPigs on May 12, but refused the assignment on May 13 and became a free agent.
Tampa Bay Rays
On May 16, 2014, Nix signed a minor league deal with the Tampa Bay Rays. He was to report to the Triple-A Durham Bulls, and would be able to opt out of the contract if not on the major league roster by July 15. Nix was released on August 1, 2014.
Pittsburgh Pirates
On August 3, 2014, Nix was signed by the Pittsburgh Pirates. Nix was designated for assignment by the Pirates on August 25, 2014.
Kansas City Royals
On August 28, Nix was claimed off waivers by the Kansas City Royals.
