Quarterback Mahomes set up the match-winning drive to end the game with a touchdown pass to Mecole Hardman Jr.
He finished with 333 throwing yards, two touchdowns and 66 running yards, while 49ers quarterback Brock Purdy threw for 255 yards with one touchdown.
The 28-year-old was given the MVP Award for the third time in his career and became the fourth starting quarterback to win three career Super Bowls.
Reid was subject to a shove from Travis Kelce in a furious exchange during the game, behaviour for which the star tight-end faced criticism.
Kelce stormed up to the Chiefs coach towards the end of the second quarter, barging into him.
The player was pulled away by a team-mate and cooled off on the sideline, where he hit his helmet against a bench.
“Man, I was fired up — I was fired up that we weren’t hitting on all cylinders,” he told ESPN after the interaction.
“I had to give ‘Big Red’ a love tap and let him know that we were all here fighting for him no matter what. I just had to tell him I loved him real quick."