Born and raised in San Diego, California, Prior engaged Tom House as his pitching tutor in high school.

A career at the University of Southern California, where he won the Golden Spikes Award, saw him become one of the top prospects in the 2001 MLB draft, when he was the second overall pick by the Cubs.

In 2003, he finished third in National League (NL) Cy Young Award voting, ranking among the leaders with 18 wins, a 2.43 earned run average (ERA), and 245 strikeouts.

Multiple injuries limited him to nine games in 2006, and he did not pitch at all in 2007 due to tears in his labrum, anterior capsule, and rotator cuff.

Using computer analysis to try to determine the ideal pitching motion, House worked with Prior on his delivery and prescribed a detailed workout regimen which the pitcher would continue to utilize as his career advanced.

[16] He threw his first career complete game on August 4, striking out 13, allowing one run, and throwing 136 pitches in a 4–1 win over the Colorado Rockies.

[17] On August 15, he struck out seven hitters in a row, tying the Cubs' record shared by Jamie Moyer and Kerry Wood.

[3][21] In his second start of the 2003 season, Prior pitched his first career shutout, striking out 12 and allowing four hits in a 3–0 win over the Montreal Expos.

[25][26][27][a] Selected as National League All-Stars in 2003,[28] both Prior and fellow right-handed pitcher Kerry Wood were dubbed "Chicago Heat" by Sports Illustrated.

[29] Sportswriter George Vecsey compared them to other famed rotation twosomes, like Warren Spahn and Lew Burdette, or Randy Johnson and Curt Schilling.

[30] According to CBS Local, sportswriters and fans criticized Cubs manager Dusty Baker on the high pitch counts of the two aces.

[30][34][35] Against his hometown San Diego Padres on August 5, Prior returned from the DL, allowing two hits and no runs in six inning and earning the victory in a 3–0 win.

[22] On September 27, he gave up two runs and struck out 10 in 6+2⁄3 innings, defeating the Pittsburgh Pirates for the win in Game 1 of a doubleheader.

[45] His ERA went up to 5.05 after he gave up seven runs over three innings in an 8–6 loss to San Diego on August 10, and Ramon Hernandez of the Padres noticed a difference.

[50] However, against the Rockies that day, 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.

Coincidentally, Hawpe had hit a three-run home run off Prior in the 2000 College World Series while playing for the Louisiana State University Tigers.

[8] Returning from the DL on June 26, Prior limited the Chicago White Sox to one hit in six innings, earning the win in a 2–0 triumph.

[53] During the 2005 off-season, after Nomar Garciaparra left the Cubs via free agency, Prior was mentioned by Ken Rosenthal of Fox Sports as part of a possible deal for Baltimore Orioles's shortstop Miguel Tejada, but this trade did not come to pass.

[61] Prior found himself competing with Wade Miller to be the Cubs' fifth starter in 2007, and he was optioned to the minor leagues before the season began.

[62] After one start in the minors, in which he gave up three runs and got the win, Prior received exploratory surgery on his right shoulder by James Andrews, a noted orthopedic surgeon;[63] the procedure showed evidence of vast structural damage.

Cubs general manager (GM) Jim Hendry said that anything provided by Prior or Wood would be "gravy" and he hoped that this would come to fruition.

[80] Unsigned to begin the 2012 season, Prior secured a minor league contract with the Boston Red Sox on May 2 and pitched in their extended spring training program.

[81] Later joining the Pawtucket Red Sox, he provided the Triple-A team with "stellar" pitching, according to Teddy Mitrosilis of ESPN, though he was walking too many hitters.

"[5] Damian Miller, his catcher with the Cubs in 2003, compared him to Curt Schilling, noting that both pitchers threw a lot of high fastballs.

[4] Sports reporter Buster Olney called his mechanics "smooth, fluid, consistent," opining that his delivery made him less of an injury-risk than teammate Wood.

[85] Chris O'Leary speculated that some of the trouble was 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.

[86] 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.

[21] Critics made Baker their "scapegoat", according to Jason Buckland of the New York Times, blaming him for overusing his young pitcher.

He said "I don't blame Dusty for what happened to me," observing that Baker had to balance how often to use the pitchers with making decisions that would help the Cubs win.

MLB columnist Tim Brown speculated that the Dodgers might groom Prior to take over as their pitching coach when Rick Honeycutt eventually retired.