He pitched for the New York Mets, Minnesota Twins, Kansas City Royals, Chicago White Sox, and Houston Astros in seven seasons in Major League Baseball (MLB).

During his minor league career, he underwent ulnar collateral ligament reconstruction before making his MLB debut with the Mets in 2006.

[1] Humber threw a shutout in the Texas University Interscholastic League Class 4A semifinals against Cedar Park High School in 2001, his senior season.

José Cruz Jr. bounced the baseball off of the wall in center field and then Lance Berkman hit the ball over the scoreboard.

[13] He was the scheduled starter in the second of the two games, which was against the Notre Dame Fighting Irish on June 17,[14] but the team could not hold a 3–2 lead in the bottom of the ninth.

[17] The 2003 season saw the development of Rice's "Big Three" rotation, featuring Humber and sophomore classmates Wade Townsend and Jeff Niemann.

[23] Upon his becoming the College World Series hero, June 26, 2003 was declared 'Philip Humber Day' in his hometown of Carthage, Texas in his honor.

[31] Humber entered the next game against the Texas A&M Aggies with the bases loaded and surrendered a first-pitch grand slam to Justin Ruggiano.

[12] Following the early exit in the Houston Regional due to the upset by the Aggies, Humber looked forward to the Major League Baseball Draft.

[37] The New York Mets chose Humber out of Rice University with their first-round pick in the 2004 Major League Baseball draft, the third overall selection.

[44] There, he clashed with Mets' pitching coach Rick Peterson, who wanted Humber to adopt a different training regimen and change the manner with which he threw the ball to the plate.

[61] Assigned to the Triple-A New Orleans Zephyrs of the Pacific Coast League (PCL), Humber had an 11–9 record and 4.27 ERA in 25 starts.

[71] The Mets, having lost eight of their previous 12 games and seen their lead over the Philadelphia Phillies in the National League East division race decrease from seven games to two, removed Pelfrey from the final rotation to give an extra day of rest to pitchers Pérez, Maine, and Pedro Martínez, and gave Humber his first Major League start on September 26, 2007, against the Washington Nationals, choosing him over Dave Williams.

How did the entire Mets' season come to depend so much on a young pitcher, Philip Humber, who had never started in the major leagues until last night?

[75] Following the 2007 season, the Mets began to discuss trading Humber to the Minnesota Twins in a package of prospects to acquire two-time Cy Young Award-winning pitcher Johan Santana.

Eligible to become a free agent after the 2008 season, Santana had rejected a proposed four-year, $80 million contract extension from the Twins.

[76] On February 2, 2008, the Mets traded Humber, along with outfielder Carlos Gómez and pitchers Kevin Mulvey and Deolis Guerra, to the Twins for Santana.

[62] At the time Baseball America ranked Guerra, Gomez, Mulvey and Humber the second, third, fourth and seventh-best prospects in the Mets organization, respectively.

[80] Humber spent most of the 2008 season assigned to the Twins' Triple-A affiliate, the Rochester Red Wings of the International League.

[88] The Twins recalled Humber in August 2009 due to an injury to Francisco Liriano,[89] but outrighted him to the minor leagues ten days later.

[91] On December 15, 2009, Humber signed a minor league contract with the Kansas City Royals, receiving an invitation to spring training.

[92] After he pitched to an 11.74 ERA in four spring training games, the Royals reassigned Humber to their minor league camp on March 22.

[64] He won the award after posting a complete game shutout against the Nashville Sounds on July 30, in which he struck out seven batters while allowing only four hits.

[46] The Royals designated Humber for assignment on December 15, 2010, in order to make room on the roster for newly signed Jeff Francoeur.

[8] On April 9, 2011, Humber won his first start with the White Sox, pitching 6+2⁄3 innings and only allowing one run in a 4–2 win over the Tampa Bay Rays.

[112] He spent time on the disabled list with a facial bruise after Kosuke Fukudome lined a baseball into his face above the right eye on August 18.

"[115] He appeared in one rehabilitation start for the Triple-A Charlotte Knights of the International League, allowing four earned runs in five innings.

[137] Humber was designated for assignment on May 12, after his record fell to 0–8 with a 9.59 ERA, he cleared waivers and was sent outright to Triple-A Oklahoma City RedHawks on May 14.

[138] After pitching in relief for the Oklahoma City RedHawks of the PCL, the Astros selected his contract on August 12, when they traded Wesley Wright to the Tampa Bay Rays.

[148] At the time of his perfect game, Humber's wife was nine months pregnant with the couple's first child,[94][128] a son named John Gregory,[148] who was born on May 1.