Ko has her work cut out for her as she will have to catch current points leader Ariya Jutanugarn of Thailand.
New Zealand's Ko won the coveted $1 million Globe bonus in both 2014 and 2015. The cash prize goes to the player who finishes on top of the season-long points race.
"For me to be in this position and have the opportunity to go for the Globe again it's a pretty cool position to be in," said Ko.
In 2014, the then 17-year-old Ko claimed her first Globe when she beat Carlota Ciganda and Julieta Granada in a playoff. She is the only player to win both the Tour Championship and the Globe in the same season.
In 2015, Ko finished tied for seventh in the tournament but it was still good enough to give her the points title.
This time Ko has her work cut out for her as she will have to catch current points leader Ariya Jutanugarn of Thailand.
Ariya will have a 500-point lead on Ko heading into the tournament which begins Thursday at the Tiburon Golf Club in Naples, Florida.
"I'm in a bit of a different position to last year. I'm not really in the driver's seat. A lot of things have to happen. I kind of need to win this week.
"For me, it's more important to have a strong finish to the season. That's what I'm mainly thinking about," said Ko, who leads the Tour for lowest scoring average at 69.6.
The top three players on the list Ariya, Ko and Canada's Brooke Henderson will automatically win the points race if they win the tournament. There are six others who have a mathematical chance of claiming the prize based on various scenarios.
Organizers have put the money in a large see-through box for the players to gawk at.
"Of course everybody likes that box," Ariya said. "I just, I don't know. No matter what is going to happen this week, this year has been a great one for me."
Ariya said her season started to turn around at the ANA Inspiration in March, when she played superbly before blowing a two-shot lead in the closing holes to allow Ko to win.
Since that event she has won five titles and finished in the top 10 12 times.
"I think at the ANA I just started to feel like everything was getting better," Ariya said.
"I learned a lot from that because I now know how to play under pressure. I know that when I?m really nervous and excited what I have to do to get through that."
American Cristie Kerr will defend her title this week at the site of her 18th career LPGA victory.
Kerr defeated South Korea's Jang Ha-Na and fellow American Gerina Piller to claim her second win of the 2015 season.