Mikan met 28-year-old rookie DePaul basketball coach Ray Meyer, who saw potential in the bright and intelligent, but also clumsy and shy, freshman. Put into perspective, Meyer’s thoughts were revolutionary, because at the time it was believed that tall players were too awkward to ever play basketball well. In the following months, Meyer transformed Mikan into a confident, aggressive player who took pride in his height rather than being ashamed of it. Meyer and Mikan worked out intensively, and Mikan learned how to make hook shots accurately with either hand. This routine would become later known as the Mikan Drill. In addition, Meyer made Mikan punch a speed bag, take dancing lessons, and jump rope to make him a complete athlete.

Mikan dominated his peers from the start of his National Collegiate Athletic Association (NCAA) college games at DePaul. He intimidated opponents with his size and strength, was unstoppable on offense with his hook shot, and soon established a reputation as one of the hardest and grittiest players in the league, often playing through injuries and punishing opposing centers with hard fouls. In addition, Mikan also surprised the basketball world with his unique ability of goaltending, i.e. jumping so high that he swatted the ball away before it could pass the hoop. In today’s basketball, touching the ball after it reaches its apex is a violation, but in Mikan’s time, it was legal because people thought it was impossible anyone could reach that high. “We would set up a zone defense that had four men around the key and I guarded the basket”, Mikan later recalled his DePaul days. “When the other team took a shot, I’d just go up and tap it out.” As a consequence, the NCAA, and later the NBA, outlawed goaltending. Bob Kurland, a seven-footer from Oklahoma A&M, was one of the few opposing centers to have any success against Mikan.

Mikan was named the Helms NCAA College Player of the Year in 1944 and 1945 and was an All-American three times. In 1945, he led DePaul to the NIT title, which at that time was as prestigious as the NCAA title. Mikan led the nation in scoring with 23.9 points per game in 1944–45 and 23.1 in 1945–46. When DePaul won the 1945 NIT, Mikan was named Most Valuable Player for scoring 120 points in three games, including 53 points in a 97–53 win over Rhode Island; his 53-point total equaled the score of the entire Rhode Island team.