He played in Major League Baseball (MLB) for the San Diego Padres, Oakland Athletics, Houston Astros and St. Louis Cardinals.

He spent his first professional season between the rookie-level Johnson City Cardinals and the short-season State College Spikes in 2006.

Before the 2009 season, Gregerson was traded to the San Diego Padres along with Mark Worrell for Khalil Greene.

[3] In 2010, Gregerson solidified his role as the regular seventh-inning relief man for the Padres, appearing before Mike Adams and Heath Bell in close games.

He temporarily moved to the eighth inning in late July and early August while Adams was on the disabled list.

On September 23, 2010, Gregerson worked a perfect seventh to set the major league record for holds in a single season with 37.

However, after multiple poor April outings by A's closer Jim Johnson, Gregerson would begin sharing the A's closing duties with fellow pitcher Sean Doolittle.

Gregerson would redeem himself on April 20, pitching a hitless inning and earning his third save of the season in a 4–1 win against the Houston Astros.

On April 22, Gregerson blew another save and took the loss in a 5–4 defeat to the Texas Rangers, further clouding the future of the A's closer role.

[12] The deal was announced in conjunction with the signing of former Padres and Athletics teammate, reliever Pat Neshek, and contained incentives to boost Gregerson's potential earnings to $21 million.

Gregerson and Alex Bregman, another Astros teammate, won the WBC participating with team USA early in 2017.

Later that year, to cap the 2017 season, Gregerson and the Astros won the World Series, marking the first championship in franchise history.