Konta becomes the first British woman to reach the championship match, where she will face 12th-seeded Caroline Wozniacki, who topped second-seeded Karolina Pliskova 5-7, 6-1, 6-1 in the other semifinal.
“I’m going to have a tough battle on my hands,” said Konta, who is assured of returning to the top 10 in the world rankings regardless of Saturday’s result. “Caroline, she makes you work for every single point.”
In a match that ended just after midnight, Konta trailed Williams 3-1 in the second set and wound up breaking her five times — in a staggering 17 chances.
Williams’ last title at Key Biscayne came 16 years ago.
Wozniacki, a part-time South Florida resident, had to rally to defeat Pliskova and won 12 of the last 14 games.
She made the women’s final for the first time in 10 tries.
“This is one of the few tournaments where I’ve never made a finals,” Wozniacki said. “I think my best result here was semifinals five years ago. It’s always been a tournament where I wouldn’t say I struggle, but I’ve just not had the results I wanted.”
The Associated Press contributed to this report.