They were challenged primarily by Chris Gotterup and Jennifer Kupcho until the par-5 17th at Tiburon Golf Club on Sunday.
Gotterup and Kupcho both missed the green in tough spots and had to work hard for par. Novak and Coughlin were in the final group behind them, and Novak poured in a six-foot birdie putt that gave them a a two-shot lead going to the final hole.
Coughlin's birdie putt helped them set a tournament record at 28-under 188.
They finished three ahead of Gotterup and Kupcho (63), Denny McCarthy and Nelly Korda (63), and Michael Brennan and Charley Hull (65).
Novak also won the Zurich Classic of New Orleans with Ben Griffin, the only team event on the PGA Tour. He joked prior to the final round it would be the "modern-day Grand Slam" to get the mixed-team title that pairs PGA TOUR and LPGA players.
"We had more holes than anyone else," Novak said, referring to the number of birdie chances down the stretch.
Novak holed a seven-foot birdie putt on the 13th, followed by a pair of 10-foot birdie putts on the 14th and 15th and what effectively was the clincher on the 17th.
In modified fourballs, both players hit tee shots, then play the other's golf ball the rest of the way with the low score counting on the card.
Novak and Coughlin each earned $US500,000 ($A752,000). It was the largest payoff for Coughlin, who won twice on the LPGA last year.
Korda missed a 10-foot birdie putt on the 18th hole that would have given her and McCarthy a little hope, and at worse put them alone in second. Korda gets one more chance at winning this year, teaming with her father next week in the PNC Championship.
Australia's Jason Day and Kiwi teammate Lydia Ko - the 2023 champions - finished 17 under after a final-round 67.
