He played 11 seasons in the National Basketball Association (NBA) for the Atlanta Hawks, Philadelphia 76ers, Los Angeles Lakers, Oklahoma City Thunder, Boston Celtics, Washington Wizards, and Detroit Pistons.

He was the 2011 Patriot League Men's Basketball Player of the Year after leading the Bison to an NCAA tournament appearance.

On August 1, 2013, Muscala signed a one-year deal with Río Natura Monbús Obradoiro of the Liga ACB.

[14] In the team's regular season finale on April 16, Muscala scored a season-high 15 points in a 111–103 win over the Milwaukee Bucks.

During the 2014–15 season, he received multiple assignments to the Fort Wayne Mad Ants of the NBA Development League.

[23] On July 25, 2018, Muscala was traded to the Philadelphia 76ers in a three-team deal involving the Hawks and the Oklahoma City Thunder.

[24] On February 6, 2019, Muscala was traded, along with Wilson Chandler, Landry Shamet and a number of future draft picks, to the Los Angeles Clippers in exchange for Tobias Harris, Boban Marjanović and Mike Scott.

[30] On January 25, 2021, Muscala made a career-high six three-pointers and scored 23 points during a 125–122 win over the Portland Trail Blazers.

[34] On February 9, 2023, Muscala was traded to the Boston Celtics in exchange for Justin Jackson and two future second-round draft picks.

[37] On June 22, 2023, the Celtics traded Muscala to the Washington Wizards as part of a three–team deal involving the Memphis Grizzlies.

[38] On January 14, 2024, Muscala was traded to the Detroit Pistons, along with Danilo Gallinari, in exchange for Marvin Bagley III, Isaiah Livers and future draft considerations.