Continuing a phenomenal run at the showpiece event, Thitikul carded a third-round eight-under-par 64 to storm to a six-shot lead in the elite 60-player field.
At 16 under, Thai compatriot Pajaree Anannarukarn and world No.2 Nelly Korda are the defending champion's closest pursuers after posting matching third-round 65s on Saturday (Sunday AEST).
But they and everyone else are seemingly playing for the second prize at the $US11 million ($A17 million) event after Thitikul surged to a 54-hole tournament scoring record of 22 under par - the tally she won with last year.
"I just trying to focus on myself and then trying to make birdies and birdies and birdies because I know a bunch of players who would be able to make a lot of birdies," the leader said.
Thitikul said she was ready for any challenge thrown down in the final round.
"Every day we face different situations, and then I think this is another situation that it can help me grow in my golf career," she said.
"So I'm happy to be able to face it because it's been a good sign, so we'll see."
Tiburon Golf Club in Naples has become Thitikul's playground, the 22-year-old playing the course in a remarkable 64 under par in her past 11 rounds.
Even after bogeying the first hole on Saturday, Thitikul rebounded with nine more birdies to have one hand on the trophy and the $US4 million ($A6.2 million) winner's cheque - the biggest in women's golf history.
Starting the day five shots back, Lee jumped out of the blocks with birdies on the opening two holes, and three in the first four, to climb to second and cut Thitikul's lead to just two shots.
But as she so often does, the 22-year-old sensation rebounded with four birdies of her own in a five-hole stretch to once again surge four strokes clear of Australia's world No.4.
Lee's prospects were long gone before a double bogey at the last hole in a two-under round of 70 left the triple major winner 11 strokes adrift of the runaway leader in a tie for ninth.
Searching for her first win of the year, after claiming seven titles in 2024, Korda will play in the final group with Thitikul on Sunday after bursting from the chasing pack with her seven-under effort.
"I'm just going to stick to my process, focus on myself, not really focus on what others are doing," the American said.
"And it's going to take a low one. It always takes a low one out here. So I'm just going focus on being present.
"Just depends on the weather as well. But this golf course is usually pretty gettable where you see always really low scores winning."
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