A consensus five-star prospect in the Class of 2017 and a McDonald's All-American, he played one season of college basketball for the Arizona Wildcats, where he was named the Pac-12 Player of the Year.

That summer, he averaged 16.5 points, 13.5 rebounds and 2.2 blocks a game for Supreme Court AAU (California) on the Under Armour circuit.

As a senior in 2016–17, Ayton led Hillcrest to a 33–6 record and national rankings across multiple outlets while averaging 26 points, 15 rebounds and 3.5 blocks.

While representing the World Select team, Ayton played at the 2016 Nike Hoop Summit, chipping in with eight points to go along with seven rebounds.

On February 23, 2018, a reported FBI wiretap revealed Arizona's head coach, Sean Miller, allegedly talked with Christian Dawkins (a key figure involved in the 2017–18 NCAA Division I men's basketball corruption scandal) to discuss paying Ayton $100,000 to allow him to enter the university, with the monetary situation being dealt with directly to him.

[23] On May 2, 2019, federal prosecutors played a wiretapped call from June 20, 2017, between Dawkins and former assistant coach Emanuel Richardson that Miller was paying Ayton $10,000 per month while enrolled at Arizona.

He'd tie that career high for points the next day alongside grabbing 18 rebounds in the Pac-12 Championship game against USC, where the Wildcats won 75–61.

[citation needed] Following Arizona's upset loss to the University at Buffalo in the Round of 64 of 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, where he was expected to be a top-tier lottery selection, if not the potential #1 draft pick.

[29] Ayton joined the 2018 NBA Summer League Suns squad on July 1, 2018, signing his rookie-scale contract five days later.

At the end of the event, Ayton averaged a double-double of 14.5 points and 10.5 rebounds in four games played and named a member of the All-Summer League Second Team.

[32] Near the end of the preseason, he led all NBA players in points, rebounds, blocks, free-throws, and field goal attempts.

[33] Ayton made his NBA debut in the season opener on October 17, 2018, and earned a double-double with 18 points and 10 rebounds, as well as a season-high 6 assists, a steal, and a block with 36 minutes played as a starter in a 121–100 win over the Dallas Mavericks.

[35] Five days later, Ayton recorded a double-double of 20 points and 14 rebounds (alongside five assists) in a 123–103 loss to the Golden State Warriors.

On October 27, he recorded 24 points on near-perfect shooting (12/13 shots made) alongside 5 assists in a loss to the Memphis Grizzlies.

On January 29, 2019, Ayton was named a member of the World Team for the Rising Stars Challenge in the 2019 NBA All-Star Weekend.

[42] On October 24, 2019, after the 2019–20 season opener, Ayton was suspended for 25 games after testing positive for a diuretic, violating the league's anti-drug policy.

[45][46] Ayton was later immediately sidelined for the next five games due to a sprained right ankle before returning again, this time coming off the bench, on December 30 in a 122–116 win over the Portland Trail Blazers.

[61] On May 23, Ayton made his NBA playoff debut, scoring 21 points on 10-of-11 shooting, to go along with 16 rebounds, in a 99–90 victory in Game 1 of the first round over the defending champion Los Angeles Lakers.

[62] In Game 2 of the Conference Finals, Ayton put up 24 points, alongside a buzzer-beating, game-winning alley-oop dunk, and 14 rebounds, in a 104–103 victory over the Los Angeles Clippers to take a 2–0 series lead.

[67] On March 23, 2022, Ayton scored a career-high 35 points on 15-of-24 shooting from the field and grabbed 14 rebounds in a 125–116 win over the Minnesota Timberwolves.

[81] On February 4, 2023, Ayton tied his season-high with 31 points on 13-of-15 shooting from the field and grabbed 16 rebounds in a 116–110 win over the Detroit Pistons.

[83] On September 27, 2023, Ayton, Toumani Camara, and a 2029 first-round draft pick were traded to the Portland Trail Blazers alongside Jrue Holiday, as part of a three-team trade that sent Damian Lillard to the Milwaukee Bucks and Grayson Allen, Jusuf Nurkić, Nassir Little, and Keon Johnson to the Phoenix Suns.

[88] On April 5, Ayton scored a season-high 34 points, along with 13 rebounds, three assists, two steals and two blocks in a 108–102 win over the Washington Wizards.

[89] Ayton is known for being a strong and athletic center at 7 feet 1 inch (2.16 m) in shoes, with a weight of 250 pounds (110 kg) being reported during his rookie season with Phoenix.

[91] He sees his game as something akin to Hakeem Olajuwon's (primarily with his footwork, which allows him to keep up with smaller players) with the competitive mentality of Kevin Garnett.

[93] Ayton represented The Bahamas in the 2016 Centrobasket, the regional basketball championship of FIBA Americas for the Central American and Caribbean subzone where he averaged a tournament-leading 11.1 rebounds per game.