He played in Major League Baseball (MLB) for the New York Mets, Minnesota Twins, Detroit Tigers, and Chicago White Sox.

After his junior year at Wichita State University, Pelfrey entered the June 2005 amateur baseball draft.

Having chosen Scott Boras as his agent, there were concerns that Pelfrey would hold out or require a higher-than-market value contract.

Pelfrey made his major-league debut with the Mets on July 8, 2006, earning the win in a 17–3 victory against the Florida Marlins.

The Mets hit grand slams (José Valentín and Carlos Beltrán) in Pelfrey's first two major league starts; this was a first in baseball history.

[3] In 2007, Pelfrey pitched well in spring training and earned a spot in the Mets starting rotation to begin the season.

Pelfrey won his next two starts in September in the midst of a close pennant race, finishing the season with a record of 3–8.

Pelfrey made his first start of the season on April 9, earning a win against the Philadelphia Phillies allowing two runs on five hits and two walks while striking out three in five innings pitched.

[citation needed] Pelfrey then followed up this performance pitching seven shutout innings against the Washington Nationals and earned the win.

However, Mike got a no-decision as the Mets won in extra innings, 5–3, after Wagner blew a 3–0 lead in the 9th by allowing a 3-run homer to Mark Reynolds with 2 outs and 2 strikes.

Later in the year, Pelfrey set a club record for most batters faced without giving up a home run, at 243; the streak was broken by Adam Dunn of the Reds.

Pelfrey went 2–0 while not allowing a run over his two starts against the San Francisco Giants and Colorado Rockies during the week ending July 13.

In his next turn, Pelfrey pitched another complete game victory, this time allowing only 6 hits and 1 run while recording his 13th win of the season.

[citation needed] On August 25, 2008, Pelfrey pitched his second consecutive complete game win, the first Met to do so since Bret Saberhagen did it in 1995.

This led fans and announcer and former Mets pitcher Ron Darling to say that perhaps Mike was pitching better in part because he had stopped using the mouthpiece, which may have been a distraction.

Pelfrey earned his first career save in the major leagues before Francisco Rodriguez got a win for the season, and Joe Mather (Cardinal's third baseman/outfielder) got the loss.

[citation needed] On April 26, it was announced that Pelfrey required Tommy John surgery on his elbow, ending his season.

He pitched in 29 games following his 2012 Tommy John surgery, his ERA finished at 5.19 in his first full year in the American League.

[19] Pelfrey spent some of the 2016 season on the Disabled List due to a lower back ailment, limiting him to 24 games (22 starts).

[20] On April 8, 2017, the White Sox signed Pelfrey to a minor league deal, assigning him to the Triple-A Charlotte.