Pennington was drafted in the first round of the 2005 Major League Baseball Draft by the Athletics. On August 12,, he was called up from the Triple-A Sacramento River Cats, and made his Major League debut that day against the Tampa Bay Rays going 0-for-3 in a 2-1 win for the Athletics. Pennington would end his 2008 season with a.280 batting average. Following the 2009 spring training camp, he was returned to the River Cats. On July 31, 2009, Pennington was called back up by the Athletics. He hit his first major league home run on August 5, against the Texas Rangers. He finished the 2009 season with 4 home runs, 21 RBIs, and a.249 batting average. He started the 2010 season in the starting role. He finished the season with 6 home runs and 46 RBI. Pennington started slow in the 2011 season, averaging.160 in his first 10 games. On August 1, he left during a game against the Seattle Mariners, after having trouble moving his muscles in his face and moving his eyes. Later that day, Pennington was diagnosed with Bell's palsy, which paralyzes one side of the face and prevents him from controlling his muscles. Although Bell's palsy can last for days, weeks, or months, he was listed as day-to-day and only missed two games. Near the end of the 2012 season, Pennington had started playing second base after the Athletics acquired Stephen Drew from the Arizona Diamondbacks to play every day shortstop, also due to the demotion of second baseman Jemile Weeks. Pennington went to the post season for the first time in his career as the Athletics won the AL West in 2012. They were eliminated in the ALDS by the Detroit Tigers in five games.
Arizona Diamondbacks
On October 20, 2012, Pennington was traded to the Arizona Diamondbacks with Heath Bell and cash considerations. Oakland received Chris Young and $500K from Arizona, and the Marlins received minor-league infielder Yordy Cabrera from Oakland. Pennington and the Diamondbacks agreed to a two-year contract worth $5 million on January 23, 2013. The contract was finalized on January 30. On April 13, 2013, Pennington was ejected for the first time in his MLB career for arguing a correctly ruled strike three call made by umpireJim Reynolds. In an 18 inning game on 24–25 August 2013 at the Philadelphia Phillies, Pennington walked five times, one shy of the Major League record. Teammate Tony Campana also walked five times. The teams drew a combined 28 bases on balls, a National League record. The Diamondbacks' 18 walks tied the National League mark. The game lasted seven hours and six minutes, the longest in franchise history for both clubs. Pennington signed a one-year, $3.275 million deal in January 2014 and avoided arbitration.
Toronto Blue Jays
On August 8, 2015, Pennington was traded to the Toronto Blue Jays along with cash considerations for minor league shortstop Dawel Lugo. He batted.160 with 2 home runs and 11 RBI in 33 games played for the Blue Jays in 2015. In game 4 of the 2015 American League Championship Series, with two out in the ninth, Pennington became the first position player in Major League Baseball history to pitch in a postseason game, giving up two hits but recording the final out in a 14–2 loss to the Kansas City Royals.
Los Angeles Angels
On November 17, 2015, Pennington signed a two-year contract with the Los Angeles Angels.
Cincinnati Reds
On February 15, 2018, Pennington signed a minor league deal with the Cincinnati Reds. Pennington earned a spot on the Reds' Opening Day roster. On May 18, 2018, he asked for and was granted his release from the organization.
Texas Rangers
On May 19, 2018, Pennington signed a minor league deal with the Texas Rangers. He elected free agency on November 2, 2018.
Oakland Athletics (Second Stint)
On February 15, 2019, Pennington signed a minor league contract with the Oakland Athletics that included an invite to Spring Training. Pennigton was one of 28 Athletics selected to go to Tokyo to play two regular season games against the Seattle Mariners. Pennington was released on March 30, 2019.
