He has played in Major League Baseball (MLB) for the St. Louis Cardinals, Washington Nationals, Detroit Tigers, Kansas City Royals and San Diego Padres.

A power pitcher, Rosenthal is known for a fastball that is difficult for hitters to pick up and reaches velocities at or over 100 miles per hour (160 km/h).

In the major leagues, he has pitched exclusively out of the bullpen, filling middle relief, set-up, and closing roles.

Due to a tear in the ulnar collateral ligament of the right elbow and subsequent reconstructive surgery in August 2017, Rosenthal missed the 2018 season, but returned to play in 2019.

[8] Said Cardinals general manager (GM) John Mozeliak of Rosenthal: "We realized we had a talent early on, when we sent him to Johnson City.

"[6] Rosenthal spent 2011 with the Quad City River Bandits, then a Cardinals Class-A affiliate, helping them to a Midwest League championship.

He started the final game of the championship series in a three-game sweep of the Lansing Lugnuts, pitching six innings, allowing four hits and two walks (BB) while striking out nine in a 6–3 victory.

[8][11] Rosenthal's 2010 and 2011 performances earned an invite to St. Louis Cardinals spring training in 2012 where his fastball lit up radar guns and the faces among club officials.

Although Mozeliak, manager Mike Matheny, and others stated that Rosenthal was ready for the major leagues, a lack of space on the roster saw him start the season with the Double-A affiliate Springfield Cardinals.

In the minor leagues, Rosenthal has appeared in 66 total games, making 48 starts, accumulating 285+1⁄3 IP, 237 hits allowed, and 98 BB for a 3.53 ERA and 1.174 WHIP.

[11] The Cardinals called up Rosenthal from Springfield for the first time on July 16, 2012, and he made his debut two days later as the 2,000th player in franchise history dating back to 1882.

[6] He posted a 2.78 ERA while striking out 25 in 22+2⁄3 IP and holding opponents to 14 hits in 89 plate appearances with a .175 batting average against.

[4] Rosenthal's successful rookie season carried over into the postseason, making him instrumental in the Cardinals' playoff run as they needed bullpen help.

An injured ulnar collateral ligament in closer Jason Motte's elbow required Tommy John surgery to repair, forcing him to miss the entire season.

Matheny reshuffled the bullpen, placing Rosenthal in the set-up role and Edward Mujica to replace Motte as the closer.

He pitched 11+2⁄3 more scoreless innings in the NLDS against the Pittsburgh Pirates, the NLCS against the Los Angeles Dodgers, and the World Series against the Boston Red Sox, striking out 18 of the 40 batters he faced and allowing just four hits.

However, with Motte still recovering from Tommy John surgery, Mozeliak announced Rosenthal would be the closer at the beginning of the next season.

The streak ended against the San Diego Padres when Jedd Gyorko singled home a go-ahead run in the ninth.

[24] With a 0.70 ERA in 37 appearances and 24 of 25 saves converted through July 6, he was selected by fellow players to his first MLB All-Star Game at Great American Ball Park in Cincinnati.

[28] In a September 28 contest against the Pirates, Rosenthal gained his 48th save, breaking the franchise single-season record, which Smith and Jason Isringhausen shared entering the season.

[31] Arbitration-eligible for the first time prior to the 2016 season, Rosenthal and the Cardinals agreed to a $5.6 million salary on January 15, 2016,[32] a raise from $530,000.

[38] Unable to agree to a contract for 2018, the Cardinals gave Rosenthal an outright release on November 6, 2017, making him a free agent.

However, he denied that he had signed a contract, stating that he would instead remain a free agent, continue rehabilitation, and work out for interested teams once he was fully recovered.

[38][40] On November 3, 2018, Rosenthal signed a one-year deal with a "conditional" option for the 2020 season, to join the Washington Nationals organization.

[56] On July 7, it was announced that Rosenthal tore a labrum in his hip that required surgery, ending his 2021 season without making an appearance for Oakland.

On March 4, 2023, Rosenthal signed a minor league contract with the Detroit Tigers organization that included an invitation to spring training.

[66] A sinking fastball that reaches the mid-90s miles per hour (MPH) and induces ground balls at a rate of over 50% was seen as a competitive advantage.

[8] However, Rosenthal also throws a straighter fastball higher in the strike zone with a regular velocity of 98 miles per hour (158 km/h) to change batters' eye level, which they have difficulty picking up.

[8] Observed one American League scout during the 2013 World Series, "He's got one of those loose-arm deliveries that creates great life on his fastball.

[77] On January 13, 2016, Rosenthal paid a surprise visit to Ethan Cortez, a 10-year-old boy who was recovering from a dog bite at St. Louis Children's Hospital.