Ayton made his debut for Arizona on November 10, 2017, and he wasted no time making an impact. In his first game, he recorded 19 points, 12 rebounds, and 3 blocks in a 101–67 win over the Northern Arizona Lumberjacks. Throughout his freshman season, Ayton continued to impress, scoring 20 points or more in 17 games and recording 23 double-doubles in 34 games.

Despite his impressive performance on the court, Ayton's college career was not without controversy. In February 2018, an FBI wiretap reportedly revealed that Arizona's head coach, Sean Miller, had discussed paying Ayton $100,000 to entice him to commit to the university. Ayton would go on to play the rest of the season, but the scandal cast a shadow over his time at Arizona.

At the end of the regular season, Ayton was named both the Pac-12's Player of the Year and Freshman of the Year, as well as becoming a member of the All-Pac-12 first team. He was also voted a consensus first-team All-American, making him one of only three freshmen to be a part of the All-American First Team that season.

After Arizona's loss in the Round of 64 in the 2018 NCAA men's basketball tournament, Ayton announced his intention to forgo his final three seasons of collegiate eligibility and declare for the 2018 NBA draft. He was selected first overall by the Phoenix Suns, where he continues to be a dominant force on the court.