Fowler and Schauffele opened with record-setting eight-under-par 62s at Los Angeles Country Club to send a catch-us-if-you can message to the rest of the 156-man field.
Lucas Herbert was the best of the Aussies out early, eight shots behind after an even-par 70, before Smith and Lee rallied to finish in red numbers with one-under 69s.
Smith and Lee are backing up after career-best PGA Championship showings last month in New York, and it showed as the in-form duo spearheaded Australia's otherwise misfiring assault.
Smith, the reigning British Open champion and world No.9, offset three bogeys with four birdies, including a rare three at the treacherous 520-yard 17th hole, to end his round tied with Lee in 25th spot.
After starting on the 10th tee, Lee also birdied the penultimate hole of his round - the par-5 eighth - to boost his prospects of joining his sister Minjee as a US Open golf champion.
Minjee won the women's equivalent last year and will defend her title next month at Pebble Beach.
Smith and Lee still have a raft of heavyweights to hunt down, including multiple major winners Dustin Johnson (64) and Rory McIlroy (65), world No.1 Scottie Scheffler (67) and 2020 champion Bryson DeChambeau (67).
But they are at least within striking distance at the year's third major.
Cam Davis, who shared fourth at the PGA Championship for his best major finish yet, posted a two-over 72 to be 10 strokes adrift of the leaders.
Despite the soft greens and unusually easy Open scoring conditions, former world No.1s Adam Scott and Jason Day could only manage disappointing three-over 73s.
Scott arrived on the back of three top-10 finishes from his past four events, but found it tough going on Thursday.
The 2013 Masters champion slumped to five over through his first 13 holes before rallying with three late birdies to at least give himself hope of making the halfway cut.Â
Day has missed the cut in his past two events, after breaking a five-year winless drought at last month's AT&T Byron Nelson Championship in Texas, and is battling once again to earn a weekend tee time.
Playing alongside Fowler, who reeled off 10 birdies to record the first 62 in US Open history, Day was unable to find his A game.
The two-time Open runner-up racked up five bogeys in his first eight holes before steadying on the back nine without making any great move.
Schauffele joined Fowler at eight under shortly after, with the pair ultimately ending the day enjoying a two-stroke lead over Johnson and fellow American Wyndham Clark, with McIlroy and Brian Harman a further shot back at five under.
Scheffler and DeChambeau are five shots off the pace in a seven-way tie for seventh.
