He played in Major League Baseball (MLB) for the Kansas City Royals, Toronto Blue Jays, Texas Rangers, Milwaukee Brewers, and Chicago Cubs.

After graduating from Halifax County High School in South Boston, Virginia, Jeffress was selected by the Milwaukee Brewers as the 16th overall pick in the 2006 Major League Baseball draft.

[citation needed] On the year, Jeffress made 10 appearances, finishing with a 1–0 record with a 2.70 ERA in 10 innings with 10 strikeouts and 6 walks.

On December 18, 2010, Jeffress was traded to the Kansas City Royals with Alcides Escobar, Lorenzo Cain, and Jake Odorizzi for Zack Greinke and Yuniesky Betancourt.

These struggles led him to be moved down to the Royals Double-A affiliate, the Northwest Arkansas Naturals on July 20, where he appeared in 9 games, starting 8, posting a 4.26 ERA in 31.2 innings, adding on 20 strikeouts as well as 22 walks and 32 hits allowed.

In the 2012 season, Jeffress split time between the Storm Chasers and Royals, as he was unable to find his footing in the majors posting a 6.75 ERA in just 13 appearances, allowing 19 hits, 14 runs and 14 walks to just 14 strikeouts in 13.1 innings.

Jeffress opened the 2014 season on the major league roster, where he struggled mightly after showing flashes the year prior.

Jeffress thrived in his return to Milwaukee, emerging as a stellar setup-man to closer Francisco Rodriguez and posting a 1–1 record with a 1.88 ERA in 29 games.

[citation needed] As the closer, Jeffress made 47 appearances, posting a 2.22 ERA with 27 saves (Tied for 4th in NL at the time) in 58 innings, striking out 35 batters while walking only 11.

On August 1, 2016, the Brewers traded Jeffress and Jonathan Lucroy to the Texas Rangers for Lewis Brinson, Luis Ortiz, and a player to be named later.

Jeffress began the 2019 season with the Brewers Triple-A affiliate, the San Antonio Missions, after suffering a shoulder injury in spring training.

On January 28, 2020, Jeffress was signed by the Chicago Cubs for a one-year, $850,000 major league contract, with the possibility he could earn an additional $200,000 based on games pitched.

[17] During the shortened 2020 season, Jeffress earned eight saves, recorded a 1.54 ERA, and held opposing hitters to a .137 batting average.

[18] On February 22, 2021, Jeffress signed a minor league contract with the Washington Nationals organization that included an invitation to Spring Training.

[27] In late June 2013 while with the Triple-A Buffalo Bisons, Jeffress was diagnosed with juvenile epilepsy, which gave an explanation to the high anxiety and seizures that he had experienced through most of his adult life.