His first career touchdown came on a 58-yard pass to wide receiver Tyreek Hill in the first quarter of a 38-28 win over the Los Angeles Chargers on September 9, 2018. He would finish the game with 256 passing yards, 4 TDs, no interceptions, a 127.5 passer rating, and was named AFC Offensive Player of the Week.

His performance for the season earned multiple awards. He was named to the 2019 Pro Bowl, he was named First Team All-Pro, 2019 Best NFL Player ESPY Award, and was named Kansas City Club 101 Awards AFC Offensive Player of the Year. He was also named the NFL MVP, the first winner for the Chiefs in franchise history.

In the 2019 season, Mahomes led the Chiefs to Super Bowl LIV, their first Super Bowl appearance in 50 years, where he helped them defeat the San Francisco 49ers 31-20.

Former Texas Tech star Patrick Mahomes brought a Lone Star staple to his new home when he joined with KMO Burger to open the first-ever Whataburger franchise in the state of Kansas. "Obviously, being from Texas, you have a lot of Texas pride. And Whataburger is kind of at the forefront of that," Mahomes told NBC Sports. "I've always ate Whataburger since I was a little kid. And then when I got older, I'd babysit my brother, and there was a Whataburger literally down the street. And we would always grab that and kind of have that while my mom was working."

The Chiefs' injury-ravaged offensive line was no match for the Buccaneers' pass rush, as Mahomes was pressured on a Super Bowl record 29 of 56 dropbacks while also being sacked three times and hit twice. Despite the pressure, Mahomes still managed to throw several long accurate passes that were dropped by their intended targets resulting in incompletions, including a toss late in the fourth quarter as Mahomes was being tripped that hit receiver Darrel Williams in the facemask.

Three days after Super Bowl LV, Mahomes underwent surgery to repair a turf toe injury he suffered in the divisional round game against the Browns.

Late in the second quarter, Mahomes reaggravated a high ankle sprain suffered in a Divisional Round victory over the Jacksonville Jaguars. The Chiefs went into halftime trailing the Philadelphia Eagles by 10, but Mahomes stayed in the game and led Kansas City to a touchdown on their first three drives of the second half, guiding the Chiefs to a 38-35 win. Despite his sprained ankle, Patrick racked up 44 rushing yards in the game, including a 26-yard scramble that put the Chiefs in range for a game-winning field goal.

In 2018, Patrick Mahomes joined Peyton Manning as the only players in NFL history to throw for more than 5,000 yards and 50 passing touchdowns in the same season.

During the 2019-2020 NFL season, Mahomes was 5-0 in games when the Chiefs were trailing by 10 or more points, giving him the most double-digit comeback wins by any quarterback in a season in NFL history. Three of those comebacks came in the NFL Playoffs against the Houston Texans, Tennessee Titans, and San Francisco 49ers, who the Chiefs defeated 31-20 to win Super Bowl LIV.

On July 6, 2020, Patrick signed a ten-year extension worth $477 million with another $26 million in potential bonuses for a total of $503 million, surpassing Mike Trout's 12-year, $426.5 million contract with the Los Angeles Angels as the largest contract in American professional sports history and making Mahomes the first professional athlete to have a half-billion dollar contract.