Perkins played his college ball for the Minnesota Golden Gophers in 2003 and 2004. With the Gophers in 2003, he went 10–2 and posted a 2.91 ERA with 117 strikeouts. In his 2004 season with the Gophers, he went 9–3 and posted a 2.83 ERA with 113 strikeouts. Perkins was drafted by the Minnesota Twins in the first round of the 2004 MLB draft, being selected 22nd overall as a compensation pick from the Seattle Mariners for their signing of Eddie Guardado.

Between 2004 and 2008, Perkins played most of his games for the Minnesota Twins minor league system. He pitched for the Elizabethton Twins, Quad City Swing, Fort Myers Miracle, Gulf Coast Twins, New Britain Rock Cats, and the AAA Rochester Red Wings. In his three seasons with Twins’ minor league teams, he pitched 386.2 innings, posting a 16–22 record with a 3.50 ERA and 380 strikeouts. He was ranked number 66 in Baseball America’s Top 100 Prospects.

Perkins made his MLB debut on September 21, 2006, against the Boston Red Sox. Coming in to relieve teammate Matt Guerrier, Perkins pitched 1.1 innings of perfect baseball. Perkins pitched in 4 regular season games in the 2006 season, all in September as a relief pitcher. He pitched 5.2 innings giving up no runs and striking out 6.

In his 2007 season, Perkins pitched in 19 games for the Minnesota Twins, all as a reliever. In 28.2 innings pitched, Perkins finished the season with a 0–0, posting a 3.14 ERA, 12 walks, and 20 strikeouts. Injuries caused his season to be short with the Minnesota Twins, as he did not pitch into June.

Perkins pitched 11 innings for the Minnesota Twins during spring training, recording one win and one loss with a 5.73 ERA. He did not make the team and was sent down to Triple-A Rochester. With the Rochester Red Wings, he pitched 33.1 innings, recording two wins, one loss, a 2.97 ERA, and 27 strikeouts. On May 7, 2008, Perkins was called up to replace injured teammate Scott Baker. He started his first major league game against the Boston Red Sox on May 10, 2008. He recorded his first major league win in a home start against the Texas Rangers on May 20, 2008.

On May 25, 2008, he pitched arguably his best MLB performance. Starting in a road game against the Detroit Tigers, Perkins recorded the win by pitching 7.2 innings, giving up 7 hits, 1 ER, 2 walks, and striking out 4.

On July 18, 2008, Perkins went six innings combined with three relievers on a three-hit shutout of the Texas Rangers. It was the first time that season that the game’s highest-scoring offense had been shut out. Perkins was 5–0 over a six start period and 7–2 with a 3.84 ERA overall.

Perkins made 17 starts with the Twins in 2009, going 6–7 with a 5.89 ERA.

Perkins threw three pitches: a four-seam fastball (95–97 mph), a two-seam fastball (93–96), and a slider (83–86). There is little variation in his pitch usage against right-handed and left-handed hitters. His velocity and effectiveness have increased since the beginning of the 2011 season, coinciding with a move to the bullpen: “Going to the bullpen allowed me to get healthy. As a starter, I had just worn down.” In 2009, as a starter, Perkins posted a 5.89 ERA and an average fastball speed of about 90 mph. His ERA has dropped considerably in the bullpen (2.48 in 2011), and his K/9 rate nearly doubled. When Perkins was a starter, he also threw a curveball and changeup.

Perkins began 2010 with the Twins’ Triple-A affiliate Rochester Red Wings. Through July, he was 4–9 with a 6.08 ERA with the Red Wings, though he showed enough improvement to get a mid-season call-up with the Twins. Perkins started one game and made three relief appearances, going 0–1 with a 9.00 ERA before being optioned back to Rochester. Perkins returned to the majors in September after rosters expanded and ended the season 1–1.

Perkins’s four-seamer has become a weapon, averaging almost 96 mph in 2011 and 2012. It also has a very high (for a fastball) whiff rate of 29% in 2012.

On March 8, 2012, Perkins signed a three-year, $10.3 million extension with the Twins. Perkins was guaranteed $2.5 million in 2013, and $3.75 million in both 2014 and 2015. There was a 2016 option for $4.5 million with a $300,000 buyout.

Perkins became the Twins closer in July 2012 after an injury to his predecessor Matt Capps. He went on to save 16 games, with an ERA of 2.56.

On March 14, 2014, Perkins agreed to a four-year extension with the Twins. In July he was named to his second All-Star game, where he was credited with the save for the American League in their 5–3 victory.

Perkins was an All-Star for the third straight year in 2015. He appeared in 60 games and had a 3.32 ERA with 54 strikeouts and 32 saves.

After another injury-shortened season, Perkins’ 2018 option was declined by the Twins with the expectation that the team would buy out his contract. He announced his retirement on January 23, 2018. On August 1, 2018, Perkins served as analyst for the Facebook Live broadcasting crew working the Indians-Twins game.