With the Chiefs trailing 20-10 in the fourth quarter, quarterback Patrick Mahomes engineered three scoring drives in just over five minutes, hitting Travis Kelce and Damien Williams with short touchdown passes to take the lead.
Williams then raced 38 yards for the clinching score, sparking wild celebration for long-suffering Chiefs fans who had not seen their team hoist the Lombardi trophy since their victory over the Minnesota Vikings in Super Bowl IV.
"We never lost faith, I mean that’s the biggest thing," said Mahomes. "Everybody on this team, no one had their head down, and we believed in each other and that’s what we preached all year long... we found a way to get it in the end.
"Those guys around us, the leaders of this team, they have the mindset that we never give up.
"We’re going to fight to the end."
San Francisco had looked well on their way to a first Super Bowl in 25 years, holding a 10-point advantage and with time running down, but few leads are ever safe from Mahomes and the explosive Chiefs offense.
In the divisional playoffs, the Chiefs fought back from 24-0 down to beat the Houston Texans and then erased a 10-0 Tennessee Titans advantage in the AFC championship.
"It was a tough loss and hurts everybody in that room," said San Francisco's Kyle Shanahan, who was trying to join his father Mike as a Super Bowl winning head coach. "Kansas City played a good game, they were better than us today.
"We can deal with that, but we're obviously disappointed."
'BEAUTIFUL TROPHY'
The 24-year-old Mahomes became the second-youngest quarterback to win a Super Bowl, adding to his growing reputation as the NFL's next superstar.
But Mahomes, who completed 26 of 42 attempts for 286 yards and two touchdowns, appeared out of sorts for nearly three quarters of the game before stepping up when it mattered to earn the Super Bowl Most Valuable Player (MVP) honors.
Mahomes is the youngest to win both the NFL and Super Bowl MVP awards.
The win was also validation for Chiefs coach Andy Reid, who had more career regular-season wins (207) than any coach without a Super Bowl win until Sunday.
"He is going to be listed as one of the all-time great coaches of history whenever he wants to be done," said Mahomes. "We wanted to get him this trophy because he deserved it.
"The work he puts in day in and day out, he is there three in the morning and leaves 11 in the evening, I don't think he sleeps."
Reid made it clear early on that he was willing to roll the dice to get his hands on the Lombardi trophy, extending both their first half scoring drives by converting on fourth downs.
The Super Bowl began on a somber note with a moment of silence in memory of Los Angles Lakers great Kobe Bryant, who was killed in helicopter crash along with eight others, including his 13-year-old daughter Gianna.
But the end of night was one of celebration as Hard Rock Stadium exploded in cheers when members of the Hunt family, the Chiefs' owners, stepped forward to accept the trophy from NFL Commissioner Roger Goodell.
The handover was particularly special given that Lamar Hunt is widely credited with coining the name 'Super Bowl'."It's a beautiful trophy," said his son Clark Hunt. "I am so happy for our players, coaches and fans."