Mahomes entered his freshman season as a backup to Davis Webb. Mahomes saw his first career action against Oklahoma State after Webb left the game with an injury, completing two of five passes for 20 yards with one touchdown and an interception. After Webb was again injured, Mahomes started his first career game against Texas. He completed 13 of 21 passes for 109 yards in the game. Mahomes would remain the starter for the final three games after that. Against Baylor, he threw for a Big 12 freshman record 598 yards with six touchdowns and one interception. For the season, he passed for 1,547 yards and 16 touchdowns with four interceptions.
Mahomes split time with the Texas Tech baseball team, where he was a relief pitcher.
Mahomes began his sophomore season at Texas Tech as the starter at quarterback. In the first game of the 2015 season, Mahomes passed for 425 yards and four touchdowns in a 59–45 win over Sam Houston State University. He followed that up with a 361-yard passing performance against UTEP, throwing for four touchdowns and rushing for two in Tech's 69–20 win over the Miners. Against TCU, Mahomes passed for 392 yards and two touchdowns in the 55–52 loss. Overall, in the 2015 season, he finished with 4,653 yards, 36 touchdowns, and 15 interceptions.
Prior to the start of the 2016 season, Mahomes announced that he was leaving the baseball team to focus on football for the entire offseason.
On October 22, 2016, Mahomes set multiple NCAA, Big 12, and school records in a 66–59 loss to Oklahoma at home. Mahomes broke the NCAA FBS records for single-game total offense with 819 yards. He also tied the NCAA record for single game passing yards with 734. He fell one short of the record for most attempts at 88. Overall, the game set NCAA records for most combined yards of total offense with 1,708 combined passing yards, and total offense by two players (the other being Oklahoma quarterback Baker Mayfield). The 125 combined points are the second most all time involving ranked teams.
Mahomes finished the season leading the country in yards per game (421), passing yards (5,052), total offense (5,312), points responsible for (318), and total touchdowns (53). For his performance, he was awarded the Sammy Baugh Trophy, given annually to the nation's top college passer, joining head coach Kliff Kingsbury, Graham Harrell, and B. J. Symons as other Red Raiders to have won the award. He was also named an Academic All-American 2nd Team by the College Sports Information Directors of America.
Mahomes announced on January 3, 2017, that he would forgo his last year of college eligibility and enter the NFL Draft.
Coming out of Texas Tech, Mahomes was projected as a first or second round pick by the majority of analysts and scouts. During the throwing drills at the NFL Scouting Combine, Mahomes' passes were clocked at 60 mph, tying Logan Thomas and Bryan Bennett for the fastest pass ever recorded at the NFL combine. Mahomes was ranked the second best quarterback by SI.com, the third best by ESPN, and ranked the fourth best quarterback by NFLDraftScout.com. After an impressive showing at the NFL Combine, representatives from 28 NFL teams were on hand to attend his pro day at Texas Tech. He became one of the fastest rising prospects during the draft process and had 18 private workouts and visits for team, which was the most for any prospect in 2017. Among the teams and coaches that he had workouts and visits with were the Arizona Cardinals head coach Bruce Arians, New Orleans Saints head coach Sean Payton, Cincinnati Bengals quarterbacks coach Bill Lazor, and coaches from the Los Angeles Chargers, Cleveland Browns, Chicago Bears, and Pittsburgh Steelers.
The Kansas City Chiefs selected Mahomes in the first round (10th overall) in the 2017 NFL Draft. The Buffalo Bills traded the 10th overall pick to the Chiefs for their first round pick, third round pick, and the Chiefs' first round pick in the 2018 NFL Draft. He was the first quarterback selected by the Chiefs in the first round since they selected Todd Blackledge seventh overall in the 1983 NFL Draft.
The Chiefs announced on December 27, 2017, that with a playoff spot and the fourth seed in the playoffs secured, they would rest starter Alex Smith and give Mahomes his first career start in their Week 17 game against the Denver Broncos. Mahomes played most of the game and helped lead the Chiefs to a 27–24 win, and completed 22 of 35 passes for 284 yards with an interception.
On January 30, 2018, the Chiefs announced they had agreed to trade Alex Smith, making Mahomes the starting quarterback for the 2018 season. In his first game as the Chiefs full–time starting quarterback, Mahomes beat division rival the Los Angeles Chargers by a score of 38–28. In the game he threw for 256 yards and four touchdowns with no interceptions and a 127.5 quarterback rating. For the performance, Mahomes was named AFC Offensive Player of the Week. His first career touchdown came on a 58 yard pass to wide receiver Tyreek Hill in the first quarter against the Chargers. The following week Mahomes threw for 326 yards, six touchdowns, no interceptions, and a passer rating of 154.8. After throwing his fifth touchdown in the game, he broke the NFL record for most touchdown passes through a quarterback's first three career games. Following his sixth touchdown pass in the game, he broke the NFL record for touchdown passes thrown in the first two weeks of the season. For his performance against the Steelers, Mahomes won his second consecutive AFC Offensive Player of the Week award becoming the first quarterback since Tom Brady in 2011 to start the season with back-to-back player of the week awards. Mahomes was named AFC Offensive Player of the Month for September. In Week 4, against the Denver Broncos on Monday Night Football, he passed for 304 passing yards and a passing touchdown to go along with a rushing touchdown in the 27–23 comeback victory. In Week 6, against the New England Patriots, he passed for 352 yards, four touchdowns, and two interceptions in the 43–40 loss on Sunday Night Football. In the following game, Mahomes and the Chiefs bounced back with a 45–10 victory over the Cincinnati Bengals. In the victory, he passed for 358 passing yards, four touchdowns, and one interception. In the next game, a 30–23 win over the Denver Broncos, Mahomes recorded a third consecutive game with four passing touchdowns to go along with 303 passing yards and one interception. During Monday Night Football against the Los Angeles Rams in Week 11, Mahomes finished with 478 passing yards, six touchdowns, and three interceptions as the Chiefs lost 51-54. Following an 89-yard touchdown pass to wide receiver Demarcus Robinson in a Week 17 game against the Oakland Raiders, Mahomes became the second quarterback in NFL history, along with Peyton Manning, to throw for 5,000 yards and 50 touchdowns. Additionally, he is one of seven players in NFL history with 5,000 passing yards in a season. He helped lead the Chiefs to a 12–4 record and their third straight division title. On January 12, 2019, the Chiefs defeated the Colts 31–13 giving the Chiefs their first home playoff win since the 1993 season. Mahomes threw for 278 yards with no interceptions and rushed for one touchdown in his first career playoff start. The win sent the Chiefs to their first AFC Championship game since 1993 and allowed the Chiefs to host the first AFC Championship game held at Arrowhead Stadium. Mahomes passed for 295 yards and three touchdowns, but the Chiefs lost to the New England Patriots in overtime 31–37.
Mahomes performance for the season earned multiple awards. He was named to the 2019 Pro Bowl, he was named First Team All–Pro, and was named Kansas City Club 101 Awards AFC Offensive player of the year.