Left-hander O'Hern, who has to win a PGA Tour title after seven full seasons on the U.S. circuit, fired a flawless nine-under-par 62 to equal the course record at CordeValle Golf Club.
The 40-year-old piled up nine birdies, including six in seven holes from the 17th after he began his round at the 10th, to end the day three strokes clear of Venezuela's Jhonattan Vegas, Belgian Nicolas Colsaerts and American Derek Ernst.
Swede Jonas Blixt was a further shot back after opening with a 66, level with Britain's Greg Owen and Americans Charles Howell III, John Mallinger and Gary Woodland.
O'Hern, best known in the United States for twice beating Tiger Woods in the early rounds of the WGC-Accenture Match Play Championship, was delighted with his form on a cold-damp day at CordeValle.
"No bogeys is always good," the Australian told reporters after covering his last nine holes in five-under 30. "I started off having to make a few par putts, four or five-footers. Once I made those, it got me going.
"I turned (at) four under and thought, 'Well, this is quite nice.' And then all of a sudden I got on a bit of a birdie binge there. I just hit the ball lovely all day and was able to hit it close."
Long regarded as one of the game's best putters, O'Hern hopes to maintain his early form at CordeValle to transform a 2012 campaign in which he has recorded just one top-10 in 23 PGA Tour starts.
"It's certainly been my toughest season as a professional," the Australian said after totalling just 23 putts in the opening round. "I made quite a number of cuts but always finished well back in the field.
"I can't really put a finger on it, but I feel like the last two, three months my game is really starting to turn around in the right direction."
Among the big names in the field, U.S. Ryder Cup captain Davis Love III opened with a 69, former world number one Vijay Singh carded a 70 and British Open champion Ernie Els returned a 71.
"All in all, I'll take 71," said South African Els, who tied for fourth at last year's Frys.com Open. "It's not the best start, but it's not the worst start. I can get into the 60s the next three rounds."
Bryce Molder, who won last year's title in a playoff with fellow American Briny Baird, launched his defence with a 71 in the second of four events in the PGA Tour's Fall Series.
- PGA Tour
- CordeValle Golf Club