Phegley was drafted by the Chicago White Sox in the first round of the 2009 MLB draft. Phegley started his professional career in 2009 at Class A with the Kannapolis hitting.224 with 9 home runs and 33 RBI in 52 games. Then during an injury-plagued 2010 season, Phegley spent time at three different levels in the White Sox system, rookie leagueBristol, Class A-AdvancedWinston-Salem and Double-ABirmingham. His totals for the 2010 season were.284, 5 home runs and 26 RBI in 48 games. He did not play the full season because he was put onthe disabled list more than once as he suffered from Idiopathic Thrombocytopenic Purpura, an uncommon blood autoimmune disorder that lowers platelet count and prevents blood from clotting. In November 2010 surgery he had his spleen removed, because doctors were of the view that the non-vital organ which is mainly a blood filter was where his platelets were being destroyed. Phegley then began the 2011 season at Double-A Birmingham but was promoted to Triple-ACharlotte for the last month of the season. He hit a combined.242, 9 home runs and 56 RBI in 116 games in 2011. Phegley spent the entire 2012 season at Triple-A Charlotte where he hit.266, 6 home runs, 48 RBI in 102 games.
Chicago White Sox
On July 5, 2013, Phegley was promoted from Triple-A after hitting.316 with 15 home runs, 18 doubles and 41 RBI. He collected his first Major League hit and RBI on a single off of Tampa Bay Rays pitcher Jeremy Hellickson on July 5, 2013. On July 7, 2013, Phegley recorded his first major league home run off of David Price. Phegley's first grand slam came four days later against Detroit's Aníbal Sánchez. In 2013, he batted.206/.223/.299 in 65 games. In 2014, he batted.216 with three home runs and seven RBIs in 11 games.
Oakland Athletics
After the 2014 season, the White Sox traded Phegley, Marcus Semien, Chris Bassitt, and Rangel Ravelo to the Oakland Athletics for Jeff Samardzija and Michael Ynoa. In 2015, he batted.249 with nine home runs and 34 RBIs in 73 games. His season concluded in mid-September because he suffered a concussion when Billy Butler inadvertently hit him in the back of his head with a bat during batting practice as Phegley was standing around the batting cage area. In 2016, he batted.256/.314/.372 with a home run and 10 RBIs in 26 games, as his season was shortened by 97 games because he was twice on the disabled list with a strained and inflamed right knee suffering from synovitis for which he had surgery. He threw out 11% of runners attempting to steal. On May 7, 2019, he caught Mike Fiers' second career No-hitter. It was the first No-Hitter of the 2019 MLB season and the 300th No-Hitter in MLB history. Phegley was non-tendered by Oakland on December 2, 2019, and became a free agent.
Chicago Cubs
On January 17, 2020, Phegley signed a minor league contract with the Chicago Cubs.