Lee, a 30-year-old South Korean who has slipped to 378th in the world, played bogey-free and closed with a birdie on the par-4 18th hole at chilly Palos Verdes.
Lee has two career LPGA Tour victories, the most recent at the Ladies Scottish Open in 2017.
She was runner-up at the ANA Inspiration in 2019 to reach a career-best 31st in the rankings but has struggled the past three years.
Megan Khang and Hyo Joo Kim each shot 66.
Nasa Hataoka, Lucy Li and Maude-Aimee LeBlanc were another shot behind.
Second-ranked Nelly Korda and her sister, Jessica, were among the group at three-under.
Hannah Green and Grace Kim are the best-placed Australians in a share of 30th place after carding even-par rounds of 71.
This is the fifth playing of the LA Open and the first at Palos Verdes, which hosted a different event, the Palos Verdes Championship, last year – won by Marina Alex, who shot a one-over 72.
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