World number 12 Ko, a two-time major champion, had not won an LPGA crown since the 2022 Tour Championship but did win last year's Saudi Ladies International and took last month's mixed team event with Australian partner Jason Day.
The 26-year-old Seoul-born Kiwi finished 72 holes at Orlando's Lake Nona, where she is a resident and member, on 14-under 274 to defeat US teen Alexa Pano by two strokes.
"I tried to work hard in the two weeks leading up to this event and to be able to win at home has been nice," Ko said.
"There were definitely nerves but a little less just because it is my home course. To see so many members come out and clap and cheer me on was the best part of this week."
Canada's Brooke Henderson was third on 278 after a closing 68 while Japan's Ayaka Furue and Americans Cheyenne Knight and Ally Ewing shared fourth on 280.
Ko, who won her first LPGA title as a 15-year-old amateur at the 2012 Canadian Women's Open, carried a two-stroke lead into the final round and stretched her advantage with birdies at the par-3 sixth and par-5 ninth holes.
After a bogey-birdie start to the back nine, Ko pitched from a penalty area to five feet and birdied the par-5 15th then withstood a closing bogey to take the $225,000 top prize.
The victory moved her within one point, or one more LPGA title, of earning a berth in the tour Hall of Fame.
"One is really close. I'm right in front of the door," Ko said. "My mindset was I'm going to do all the things I can do and try and do a good job with that and if it happens it happens. If not, it's just not meant to be mine.
"To have myself a better chance of it now after winning this week, is definitely really cool but nothing changes internally where I'm not going to get to crazy about what may happen, just try and play some solid golf and see where that puts me."
Ko won her first event last year in Saudi Arabia but went winless on the LPGA Tour.
"It kind of went sideways very quick," she recalled. "I'll not get too cocky."
She will play in next week's Drive On Championship in nearby Bradenton.
"I'm excited to go out there. It's a new course for me," Ko said. "Maybe I can take all the goods from this week and take it to next week."
Pano, whose only LPGA title came last August on her 19th birthday at the Handa World Invitational in Northern Ireland, made bogeys at the par-3 sixth and 13th holes.
She answered with a birdie at nine and three birdies in four holes starting at the 14th but it was too little and too late to catch Ko.
