The centerpiece of the 2011 trade that sent Hunter Pence to Philadelphia, Baseball America named Singleton the Astros top prospect heading into the 2012 season. After testing positive for marijuana twice in 2012, Singleton was suspended for the first 50 games of the 2013 season. Jon struggled to get back on track and suffered through a difficult 2013 season. A return to form in 2014 prompted the Astros to sign Singleton to a multi-year contract worth a guaranteed $10 million, and called him up to the big leagues.

Singleton hit 21 homers for AA Corpus Christi and posted years of 22 and 20 homers at AAA Fresno but could not adjust to major league pitching, batting .171 with 14 homers in call-ups during the 2014 and 2015 seasons. He was released in 2018 and was paid the remainder of his contract.