Mahomes was born in Tyler, Texas, to parents Pat Mahomes, then an MLB pitcher, and Randi Mahomes on September 17, 1995. Mahomes attended Whitehouse High School in Whitehouse, Texas. He played football, baseball, and basketball. He believes that training pitching and playing basketball also improved his quarterback throwing skills. In football, he had 4,619 passing yards, 50 passing touchdowns, 948 rushing yards and 15 rushing touchdowns as a senior. In baseball, he threw a no-hitter with 16 strikeouts in a game his senior year. He was named the Maxpreps Male Athlete of the Year for 2013–2014.

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 Pittsburgh 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.

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.

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 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 the fourth best 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 official team visits, 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.

On July 20, 2017, the Chiefs signed Mahomes to a fully guaranteed four-year, $16.42 million contract that included a signing bonus of $10.08 million.

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.

In the Chiefs’ first game against the Jacksonville Jaguars, Mahomes threw for 378 yards and three touchdowns despite star receiver Tyreek Hill getting injured in the first quarter and Mahomes spraining his ankle in the second quarter. In Week 2 against the Oakland Raiders, Mahomes threw for 278 yards and four touchdowns in the second quarter alone, which was the most passing yards in any quarter since 2008. Mahomes finished the game with 443 yards, and was named AFC Offensive Player of the Week. For the second consecutive season, Mahomes was named AFC Offensive Player of the Month for September after leading the Chiefs to a 4–0 start with ten passing touchdowns and no interceptions. Mahomes dislocated his patella in the Chiefs Week 7 game against the Denver Broncos. The following day, an MRI revealed no significant structural damage to his knee and he was initially expected to miss at least three weeks. He returned just two weeks later in Week 10 against the Tennessee Titans, throwing for 446 yards and three touchdowns with no interceptions. However, despite Mahomes’s performance, the Chiefs lost 35–32. Mahomes ran for a career-high 59 yards, but threw for a career-low for games he finished with 182 yards in the Chiefs’ Week 11 victory over the Chargers. In a Week 16 win over the Chicago Bears on Sunday Night Football, Mahomes celebrated by counting to 10 on his fingers, alluding to the fact that he was the 10th overall pick in the 2017 NFL Draft and that the Bears could have drafted him with the second pick instead of drafting Mitchell Trubisky. He finished the season with 4,031 yards and 26 touchdowns with only five interceptions. He helped lead the Chiefs to their second consecutive 12–4 record and first round bye, as well as their fourth consecutive division title. He was selected to the 2020 Pro Bowl, though he did not play due to his participation in Super Bowl LIV.

On January 30, 2018, the Chiefs announced they had agreed to trade Alex Smith to the Washington Redskins, 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.

On January 12, 2019, the Chiefs defeated the Indianapolis Colts in the Divisional Round by a score of 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 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 37–31.

On April 30, 2020, the Chiefs picked up the fifth-year option on Mahomes’ contract. On July 6, he signed a 10-year contract extension worth $477 million with another $26 million in potential bonuses for a total of $503 million, which extends his contact through the 2031 season. The contract is the largest contract in American professional sports history surpassing Mike Trout’s 12 year $426.5 million contract of the Los Angeles Angels. Mahomes is also the first professional athlete to have a half a billion dollar contract. In the Chiefs week 2 win over the Los Angeles Chargers, he earned the fourth 4th quarter comeback of his career. The Chiefs trailed 9–17 entering the fourth quarter. Mahomes led the comeback to win the game in overtime 23–20. The comeback was his sixth double digit deficit that he overcame to win, including the playoffs, which is an NFL record.. In Week 3 win over the Baltimore Ravens, he became the fastest quarterback to surpass 10,000 career yards. It took him 34 games, eclipsing the mark set by Kurt Warner. He was named the AFC Offensive Player of the Week for his performance of 385 passing yards and five total touchdowns (four passing and one rushing) in Week 3. In Week 8, against the New York Jets, he threw for 416 yards and five passing touchdowns in the 35–9 victory. On November 4, 2020, Mahomes was named the AFC Offensive Player of the Week for his performance in Week 8. In Week 9, against the Carolina Panthers, he had 372 passing yards and four passing touchdowns in the 33–31 victory.

On September 1, 2020, Mahomes proposed to Brittany Matthews, his high school sweetheart, in a suite in Arrowhead Stadium, the same day Mahomes received his Super Bowl Championship ring. Matthews had a brief professional soccer career playing for UMF Afturelding and then became a certified personal trainer. Mahomes and Matthews live in Kansas City, Missouri. On September 29, 2020, the couple announced that they were expecting their first child together. On October 21, 2020, they announced that they were having a girl. That day, Mahomes tweeted “#girldad” along with a video of the gender reveal, referencing a hashtag that became popular after Kobe Bryant’s death.

After winning Super Bowl LIV and earning the Super Bowl MVP on February 2, 2020, Bloomberg News estimated that Mahomes would earn as much as an additional $7 million per year in additional income from endorsements as the most marketable player in the NFL.

Mahomes and Tyrann Mathieu started a voter registration project in Kansas City. The project encourages Kansas City residents to register to vote in the 2020 Presidential Election. He also worked with the Chiefs to encourage players to vote. He also joined LeBron James’ Rock the Vote initiative to encourage people to register and vote.

On July 28, 2020, Mahomes joined the Kansas City Royals ownership group as a minority stakeholder.