In his first six years in the league, Kansas City quarterback Patrick Mahomes has pulled off a career’s worth of surprises, trick plays and comebacks. So with 2 minutes 37 seconds remaining in the fourth quarter and his Chiefs trailing by just a point at home against the Detroit Lions, Mahomes seemed poised to mount yet another game-winning drive.

But on Thursday night, Mahomes was playing under unusual circumstances. With his favored target, tight end Travis Kelce, out with a knee injury and the longtime offensive coordinator Eric Bieniemy replaced by Matt Nagy, Mahomes was unable to spin his familiar magic.

Receiver Kadarius Toney, uncontested, dropped a pass on the first play of the drive, and a completion to receiver Skyy Moore was called back because of an offensive holding penalty. Three more incompletions and a penalty forced the Chiefs to hand over the ball on downs, allowing the Lions to hold on for a 21-20 upset victory in the N.F.L.’s season-opening game.

“There were some good things on offense, but we have to be more consistent,” Chiefs Coach Andy Reid said. “It’s unusual for us to drop that many passes anywhere anytime.”

It was a shocking result, and not just for the Chiefs fans who reveled in a pregame celebration of their team’s latest Super Bowl championship, from February. Mahomes, the team’s star, the undisputed king of active quarterbacks after the retirement of Tom Brady, looked human. Entering his seventh season, Mahomes has already won two Super Bowl titles in three appearances, and two Most Valuable Player Awards.

“It’s embarrassing for me to lose any time,” Mahomes said. “It’s cool for the fans to see the banner dropped, but this is a whole new year.”

Detroit’s win continued a surprising streak dating back to last season, when the Lions won eight of their final 10 games, including an upset of the division-rival Packers that knocked Green Bay out of playoff contention.

Entering his third season as the Lions’ head coach, Dan Campbell has made a hallmark of surprising and bold play calls, which he went to early against Kansas City. In the first quarter, Campbell called a fake punt with the Lions on their own 17-yard line. The ball was snapped directly to linebacker Jalen Reeves-Maybin, who ran up the middle of the field for 3 yards and a first down. Quarterback Jared Goff zipped short passes the rest of the drive, finding Amon-Ra St. Brown for a 9-yard score to give the Lions a 7-0 lead following the extra point.

Despite an uneven performance by his standards, Mahomes, who finished with 226 yards on 21 of 39 passing, mustered his teammates at key moments. On the drive following the Lions’ first score, Mahomes targeted seven different receivers to march Kansas City on a 75-yard touchdown drive.

The Lions botched a touchdown drive when receiver Marvin Jones Jr. fumbled in the red zone. With the game knotted at 7 before halftime, Mahomes hit receivers Marquez Valdes-Scantling and Justin Watson on back-to-back plays for 34 and 26 yards. He then found the backup tight end Blake Bell alone at the goal line for a touchdown.

The Lions caught a break in the third quarter when Brian Branch picked off a Mahomes pass that popped out of Toney’s hands. Branch raced 50 yards into the end zone to knot the score at 14. The Lions, it seemed, were not going to go away easily.

The Lions also hurt themselves. They were charged with a 41-yard pass interference penalty on a Kansas City drive late in the third quarter. After two more Mahomes passes were dropped, the Chiefs settled for a field goal to take the lead, 17-14. Kicker Harrison Butker added another field goal early in the fourth quarter.

The Lions went ahead, 21-20, midway through the fourth quarter when running back David Montgomery bulled 8 yards into the end zone.

On the Lions’ next drive, Campbell again made an aggressive call by opting to go for it with the Lions parked at the Chiefs’ 45-yard line on fourth-and-2. He was perhaps emboldened with Chris Jones, the Chiefs’ All-Pro pass rusher, watching the game from a suite in the stadium amid a contract dispute and Goff on his way to a 253-yard performance.

But Goff’s attempt was batted down at the line by Chiefs safety Justin Reid, giving Mahomes plenty of time to regain the lead. That was until he was undone by his teammates.

The Lions left Arrowhead Stadium with a statement victory, with Goff beckoning cheers from the stands. Detroit has not won its division in three decades and hasn’t made the playoffs in six seasons. The Lions sank to a 1-6 start to begin the 2022 season, many of the losses decided by one-score margins.

“We’re tired of being on the poor side of things, where you walk away from these games and you know it’s a close one but you lose,” said Aidan Hutchinson, the Lions’ second-year defensive end. “And I think we’re tired of it, man. And, man, I think we’re coming this season, dude.”

Despite the loss, the Chiefs remain a team to be feared. Mahomes, the most talented player of his generation, is determined not to rest on his laurels. Before the game, he was asked if Kansas City, which appeared in three Super Bowls during Mahomes’s first five seasons as the full-time starter, is a dynasty. No, he said, the team would need to win a third Super Bowl to earn that status.

As Thursday’s loss showed, to earn a third ring, Mahomes will need a little help.