In his second game against the New York Mets, Zimmermann won his second game in as many starts, becoming the first Nationals/Expos pitcher to win his first two starts of his career since Randy Johnson did so in 1988. Coincidentally, Zimmermann was the losing pitcher in Johnson’s historic 300th win on June 4, 2009.

In 2008, Zimmermann had a combined 10–3 record with a 2.89 earned run average (ERA) with the Potomac Nationals of the Class A-Advanced Carolina League and the Harrisburg Senators of the Class AA Eastern League, and in July was named to the Eastern League All-Star team. He finished the season leading the organization in wins, strikeouts, and earned run average, and was the MILB.com Nationals pitcher of the year.

Zimmermann was rated the Nationals’ best prospect going into the 2009 MLB season, according to Baseball America. In 2009, Zimmermann made the Nationals’ roster as the fifth starter; however, the Nationals did not need him in the rotation until mid-April, so Zimmermann opened the season with the Triple-A Syracuse Chiefs. Zimmermann’s contract was purchased on April 20, 2009, and he made his major league debut that night, after a two-plus hour rain delay, against the Atlanta Braves. He pitched six innings, allowing two runs on six hits, with three strikeouts and a walk, earning the victory.

Zimmermann experienced elbow pain, and in July landed on the disabled list. After attempted rehab, in August 2009 Zimmermann was diagnosed with a torn ulnar collateral ligament and underwent Tommy John surgery, expecting to miss 18 months. He finished his rookie season of 2009 going 3–5 with a 4.63 ERA in 16 starts.

In 2010, he made quick progress. Over four minor league levels, he started 10 games in limited play, racking up just 39.2 innings, but compiling a solid record: 1.59 ERA, 27 hits allowed, 31 strikeouts, and just six walks. On August 26 he was recalled to make his 2010 debut back in the big leagues, where Zimmermann got a no-decision in an eventual win by the Nationals over the Cardinals. On this same day, the Nationals learned that their other young pitching phenom, Stephen Strasburg, would need Tommy John surgery and would be out for 12–18 months. In Zimmermann’s second return start, however, five days later, he pitched six shutout innings, allowing only one hit, no walks, and striking out nine, a personal best. He also became the first National to get through six innings facing only 18 batters. Zimmermann finished the 2010 year 1–2 with a 4.94 ERA in seven starts.

On May 6, 2011, Zimmermann pitched an immaculate inning versus the Florida Marlins at Sun Life Stadium. He finished the 2011 year 8–11 with a 3.18 ERA.

On May 28, 2012, Zimmermann hit his first career home run off of Miami Marlins pitcher Carlos Zambrano. Zimmermann became the third Nationals pitcher named NL Pitcher of the Month during the 2012 season when the selection was announced on August 2, 2012. During July he went 4–0 with an MLB-best 0.97 ERA. He gave up 27 hits in 37 innings and struck out 31 compared to 4 walks. He finished the 2012 season 12–8 with a 2.94 ERA.

Zimmermann hurled his first career shutout on April 26, 2013, with a one-hitter against the Cincinnati Reds. It was the second straight one-hitter by Nationals pitching in the series, marking the first occasion since 1917 that a Washington team achieved that streak, and the first time since 1900 that the Reds were victimized that way.

In 2013, Zimmermann was named to his first All-Star Game, but chose not to play due to stiffness in his neck. He finished the season with a career high in wins, going 19–9, while also posting a 3.25 ERA and 161 strikeouts in a career-high 213 ⁄3 innings over 32 starts. His wins total tied with Adam Wainwright for the National League lead.

On September 28, 2014, the last day of the regular season, Zimmermann threw the first no-hitter in Washington Nationals history, a 1–0 win over the Miami Marlins and Henderson Alvarez, the pitcher who threw the final no-hitter of the 2013 season. Zimmermann faced only one over the minimum in the game; only a fifth inning walk to Justin Bour and a seventh inning third strike wild pitch that allowed Garrett Jones (who was subsequently picked off) to reach first base separated him from a perfect game. This was also the first time in MLB history that a no-hitter had been thrown on the final day in two consecutive seasons. He finished the season with a 14–5 record and a 2.66 ERA, striking out a career-high 182 batters in 199 ⁄3 innings.

On November 30, 2015, the Detroit Tigers signed Zimmermann to a five-year, $110 million contract.

On April 11, Zimmermann was struck in the face by a line drive by Jason Kipnis. Zimmermann was taken to the hospital, and was diagnosed with a bruised jaw, but made his next start. On May 6, after making seven starts in the 2018 season, Zimmermann was placed on the 10-day disabled list with a right shoulder strain. He returned to the rotation on June 16. For the 2018 season, Zimmermann made 25 starts, compiling a 7–8 record with a 4.52 ERA and 111 strikeouts in 131 ⁄3 innings pitched.

Zimmermann opened the season as the Tigers Opening Day starter. He was placed on the disabled list on April 26, 2019 due to a UCL sprain. He returned to MLB action on June 19, starting and pitching four innings against the Pittsburgh Pirates. Zimmermann finished the 2019 season with a 6.91 ERA and a dismal 1–13 record, becoming the first Tiger pitcher since at least 1908 to post fewer than two wins in a season with at least 20 starts.

On July 18, 2020, it was announced by the team that Zimmermann would begin the 2020 season on the 45/60 day disabled list due to a right forearm strain. With the 2020 Detroit Tigers, Zimmermann appeared in 3 games, compiling a 0-0 record with 7.94 ERA and 6 strikeouts in 5.2 innings pitched.