The 36-year-old fired a three-under-par 69 at Trump International Golf Club in Rio Grande to post a 16-under total of 272.
Japanese sensation Ishikawa, seeking his first victory on the U.S. circuit, had to settle for second place after closing with a six-birdie 68.
American Boo Weekley (66) and Swede Henrik Stenson (71) were a further stroke back at 13 under in a tie for third.
McNeill, who claimed his maiden PGA Tour victory as a rookie at the 2007 Frys.com Open, held a one-stroke lead going into Sunday's final round but trailed early finisher Ishikawa by one with two holes to play.
"I was not aware that Ryo Ishikawa had the lead," McNeill told reporters after mixing six birdies with three bogeys. I knew that I needed to make a few birdies coming in, and that's the only thing I could really control.
"After I birdied 16 and was walking up to the 17th green after I hit my second shot is when I saw that he had the lead with me.
"So I had about a 10-footer there, and I said: 'Well, I need to make it.' So it was not like it was an easy cake walk, but it was a nice way to win."
McNeill rolled in birdie putts from 25, 10 and four feet at the 16th, 17th and the last to seal victory.
"I made three birdies in the last four holes, and it was great for me to be very close to the winning experience," the 20-year-old said.
"It felt like a dream sometimes. If I get the next chance (to win), I will grab it for sure."
(Reporting by Mark Lamport-Stokes in Indian Wells, California; Editing by Julian Linden)