Keys' 6-3 2-6 7-5 victory stopped Belarusian Sabalenka's bid to become the first woman to claim three straight Melbourne Park titles since Swiss Martina Hingis from 1997-99 and ended her 20-match winning streak on Rod Laver Arena.
Victory made the 29-year-old the fourth-oldest first-time Grand Slam winner in the professional era, behind only Flavia Pennetta, Ann Jones and Francesca Schiavone.
"Everything happens for a reason," Keys said with champagne in her hand and the Daphne Akhurst Memorial Cup beside her.
"I had to go through some tough things. It forced me to look at myself in the mirror and try to work on the internal pressure that I was putting on myself. I got to the point where I was proud of myself and my career with or without a Grand Slam.
"I didn't need it to feel like I had a good career or that I deserved to be talked about as a great tennis player.
"Finally letting go of that internal talk I had gave me the ability to actually go out and play some really good tennis, to actually win a Grand Slam."
Sabalenka made a couple of untimely double faults to drop serve in the opening game and looked slightly off colour in the early exchanges as Keys heaped pressure on the top seed with a dipping crosscourt winner en route to a double break.
The 19th seed rode her luck after a net cord winner and went ahead 5-1 in 20 minutes, before conceding a break with a wayward backhand, but Sabalenka gifted Keys a set point with her fourth double fault.
Hitting harder than her opponent on both flanks, Keys blasted the 11th of her 29 winners with a backhand down the line to take the set, but Sabalenka began to mix up her game in the next set and sliced her way through to level the match.
Both players relied on their powerful serves and shot-making to remain level until 5-5 in the decider but there was one final momentum shift as Keys produced blistering winners to claim the next two games and the biggest triumph of her career.
--Reuters--