In 2001, Prior re-entered the draft, and was considered by some to be the top prospect, but the Minnesota Twins, who had the top pick, were warned that Prior did not want to play for them. Fearing signability problems, the Twins opted to take local talent catcher Joe Mauer, leaving Prior to be taken 2nd overall by the Chicago Cubs. The Cubs had also been considering drafting Georgia Tech third baseman Mark Teixeira, who went fifth to the Texas Rangers. The Cubs signed Prior to a contract for $10.5 million, which stood as the record amount for a draft pick until 2009.
In 2003, Prior finished third in the National League's Cy Young Award voting after compiling an 18–6 win-loss record despite missing three starts after an on-field collision with Atlanta Braves second baseman Marcus Giles. Prior and Giles had both been chosen to play in the All-Star Game, but were forced to miss the game as a result of their injuries. Prior and fellow right-handed pitcher Kerry Wood were dubbed "Chicago Heat" by Sports Illustrated, and the name stuck, as the twosome were dominant in leading the Cubs to an 88-win season and a division title. However, sportswriters and fans began to criticize Dusty Baker on the high pitch count of the two pitchers. Despite the concerns, Prior and Wood continued to pitch high counts throughout the season. In 2003, Prior averaged 113.4 pitches per starts in regular season. In the month of September, Prior recorded 126 pitches per start. Prior averaged another 120 pitches in games in the postseason and struggled with an injury the next season. Pundits often blame Baker for ruining the careers of both pitchers.
After Prior's stint on the disabled list came to an end, he compiled a 10–1 record, and pitched against former Cub Greg Maddux in the first round of the playoffs. The Cubs beat the Atlanta Braves in the first round, but lost to the eventual World Series Champion Florida Marlins in the NLCS, a tightly contested seven game series. Prior, who was the winner in Game 2, was on the mound for the infamous Steve Bartman/Moisés Alou foul ball incident in Game 6. At the time, the Cubs were nursing a three-run lead in the 8th inning, and were only five outs away from playing in the World Series. Prior struggled with his command and gave up the lead with the aid of poor defensive play, most notably the booted double play grounder and error by shortstop Alex Gonzalez. The Marlins scored eight runs in the 8th inning, winning 8-3 in Game 6, and also went on to win the deciding Game 7 of that NLCS and ultimately beat the New York Yankees in the World Series.
Prior was forced to miss the first two months of the 2004 season due to an achilles tendon injury. There were published reports stating that Prior would need reconstructive Tommy John surgery on his elbow, but both Prior and the Cubs denied this, saying that his Achilles tendon injury is the only reason he missed time in 2004. After coming off the disabled list Prior did not pitch up to expectations, leading to more speculation about the health of his arm. However, towards the end of the 2004 season, Prior seemed to return to form. He struck out a career high 16 Cincinnati Reds in his last start of the season. Prior finished 2004 with a 6-4 record and a 4.02 ERA in 21 starts.
Prior's 2005 season was again marred with missed games due to injuries. After starting the season on DL again, he returned and pitched well in the early part of the season. However, on May 27, Prior was hit on his right (pitching) elbow by a 117-mph comeback line drive off the bat of Brad Hawpe, giving him a compression fracture. This sent him to another stint on the DL. Coincidentally, Hawpe, when playing for LSU in the 2000 College World Series, had hit a three-run home run off Prior that eliminated USC from contention that year. Prior finished the 2005 season with an 11–7 record in 27 starts.
During the 2005 off-season, after Nomar Garciaparra left the Cubs via free agency, Prior was mentioned as part of a possible deal for Baltimore Orioles's shortstop Miguel Tejada, but this trade did not come to pass. His bad luck would continue in Spring Training of 2006 when he was put on a slow throwing program. After feeling stiffness in his throwing shoulder, he was diagnosed with a strained shoulder. He was placed on the 15-day disabled list, missing the first two months of the 2006 season. His debut came on June 18, when he was shelled by the Detroit Tigers, giving up six runs in the first inning and lasting just 3.2 innings before being pulled. Prior was 0–4 in four starts with a 7.71 ERA, until he was once again put on the disabled list July 14, after straining his left oblique muscle while taking batting practice. He returned on July 21 to play against the Washington Nationals. He pitched only 3.1 innings before he was pulled out of the game. On August 14, Prior was placed on the disabled list (tendinitis) for the remainder of the season. He finished 2006 with a 1–6 record and a 7.22 ERA.
In the offseason, the Cubs reported that Prior suffered from a "loose shoulder" which could lead to injuries and meant he had to do more conditioning work. Eligible for arbitration, Prior proceeded to ask for a pay raise from his 2006 salary of $3.65 million to $3.875 million for 2007. The Cubs avoided arbitration with Prior when he settled for a one-year $3.575 million contract for 2007.
After one start in the minors, in which he gave up three runs and got the win, Prior had James Andrews, a noted orthopedic surgeon perform exploratory surgery on his right shoulder, which showed Prior to have structural damage. Prior missed the rest of the 2007 season after going through season-ending surgery. Cubs GM Jim Hendry said that anything provided by Prior or Wood would be "gravy" and he hoped that this would come to fruition. Prior was non-tendered on December 12, 2007, ending his tenure with the Chicago Cubs.
On December 26, 2007, Prior agreed to a $1 million, one-year, incentive-laden contract with the San Diego Padres. Prior had hoped to pitch again by May or June of the 2008 season, but a shoulder tear during his rehab at the end of May 2008 required surgery that forced him to miss his second consecutive season.
On January 13, 2009, an elated Kevin Towers announced "Ladies and gentlemen, we're bringin' em back." Prior agreed to a one-year minor league contract with the San Diego Padres. The minor league deal included a $1 million option that would have been lifted if Prior pitched in the major leagues in 2009. He was released from his contract on August 1, 2009 after not having been called up all season.
On September 3, 2010, he signed with the Texas Rangers on a minor league contract. Prior stated his desire to return to the big leagues, four years after last being on a major league squad; he hoped to catch on with the Rangers as a long/middle relief pitcher.
Prior signed a one-year minor league contract with the New York Yankees for the 2011 season. Prior was assigned to start the year with the Class A Tampa Yankees in Florida rather than joining the colder weather Scranton/Wilkes-Barre Yankees in order to work on his transition to a relief pitcher. His year would end after the promotion to AAA with a groin injury. He was granted free agency on November 2, 2011.
Prior's pitching mechanics were the subject of much attention throughout his career. As a prospect, his symmetrical, seemingly effortless delivery was widely regarded as mechanically efficient and sound. Prior's former personal pitching coach Tom House labeled the right-hander a "can't-miss" prospect. However, after Prior suffered a series of debilitating arm injuries, many experts re-examined Prior's delivery.
As easy and flowing as Prior's pitching mechanics seemed to be, his arm action contained elements that some analysts believed to be hazardous. According to Chris O'Leary, a pitching mechanics analyst, Prior's injury problems were largely derived from his arm action. More specifically, they were due to Prior's Inverted W arm action, in which he lifted his elbows above and behind the level of his shoulders, with the forearm pointing down. According to O'Leary, this created a timing problem that placed an undue stress on the muscles and ligaments of the shoulder and elbow because the arm got up to the "cocked position" too late.
Similarly, Dick Mills, a former major league pitcher and co-author of The Science and Art of Baseball Pitching and Pitching.com, speculated that Prior's injuries were a result of a movement known as scapular loading. Scapular loading is a movement in which a pitcher's shoulder blades are pinched together and elbows are taken behind, and sometimes above, their shoulders. The idea that scapular loading is dangerous has been disputed by some in the field of athletic training.