He committed to play at California State University, Long Beach a few months before the 2009 Major League Baseball Draft.

He had been projected for selection as high as the second round of the draft, but his senior year statistics caused him to fall.

[4] On July 29, 2011, the Phillies traded Singleton, Jarred Cosart, Josh Zeid, and Domingo Santana to the Houston Astros in exchange for Hunter Pence.

On June 8, Singleton lined his first career grand slam off of Glen Perkins of the Minnesota Twins at Target Field to help the Astros to a 14–5 win.

It was initially ruled an out by the home plate umpire, but was later reversed following a challenge by Astros manager Bo Porter.

[19] On May 13, 2015, Singleton recorded 10 RBIs, including a grand slam and two-run home run against the Albuquerque Isotopes.

[21] He played the 2017 season with the Corpus Christi Hooks of the Class AA Texas League, and led all minor leaguers with 500 or more plate appearances with a walk percentage of 21.4%.

In a statement to the Associated Press, Singleton admitted that he had a substance abuse problem: "At this point, it's pretty evident to me that I'm a drug addict.

[27] He spent the 2022 season with the Triple-A Nashville Sounds, batting .219/.375/.434 in 456 at-bats, including 24 home runs and 87 RBIs.

[37] On June 24, 2023, Singleton rejoined the Houston Astros organization via a minor league contract and was subsequently assigned to Triple-A Sugar Land Space Cowboys.

[38] Singleton was called up to the majors on August 8, after a .333/.446/.692 performance over 33 games at Sugar Land, including 12 home runs, 28 RBI, 26 walks and 34 strikeouts.

He pinch hit in the ninth inning against closer Félix Bautista, drew a walk, and scored on a go-ahead grand slam by Kyle Tucker that led to a 7–6 Astros win.

[a][41] On September 10, 2024, Singleton hit his first major league triple in a game versus the Oakland Athletics at Minute Maid Park.

[42] For the 2024 regular season, Singleton batted .239/.321/.386, 13 doubles, 13 home runs, 42 RBI, 47 BB, and 111 strikeouts; he played in 119 games and accrued 405 plate appearances, both career highs.