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. He made only six appearances in the minor leagues before debuting with the team in 2002. 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. Helping the Cubs win the NL Central title, he outpitched Greg Maddux in the NL Division Series and won Game 2 of the NL Championship Series, but he was on the mound for Game 6 when Steve Bartman prevented Moisés Alou from catching a foul ball (Bartman was one of several fans who attempted to catch the foul ball that was clearly in the stands).