Granada carded a two-under-par 70 as she earned the outright lead at the Ritz-Carlton Golf Resort in Naples, Florida on Saturday.
The Paraguayan - without a win on the LPGA Tour since taking out the now defunct ADT Championship in 2006 - is a stroke clear of American Morgan Pressel and Spaniard Carlota Ciganda.
"I played pretty well today; super consistent," said Granada, who went bogey-free on the front nine after holing two birdies.
"I hit a lot of fairways and I hit a lot of greens. I made some good putts out there. So I'm looking forward to tomorrow, see what tomorrow brings."
Granada, who is in the race for the $1million bonus for the Race to the CME Globe title, added: "I'm aware of what’s going on. I like to know where I stand.
"Like I said before, I just have to keep playing my game and trust my game, that it’s good enough to win out here."
Pressel (70) and Ciganda (71) are tied at eight under through 54 holes in Florida.
After bogeying her first hole, Pressel recovered to go blemish-free for the remainder of the round.
Ciganda had back-to-back bogeys from the opening three holes, though four birdies afterwards helped her into a share of second.
German Sandra Gal (70) is in sole possession of fourth spot at seven under, while New Zealand's Lydia Ko (68) and South Korean Ru So-yeon (70) are a shot further back.