The 23-year-old, who missed a birdie putt last week at Palos Verdes Golf Club to join a playoff eventually won by Nelly Korda, was in fine form again - this time at the Ford Championship at the Seville Golf and Country Club.
Ruffels had seven birdies, an eagle and a bogey in an 8-under 64 that left her just one stroke behind Thailand's Pajaree Anannarukarn in the opening round.
After turning in 32, which included an eagle on the fifth, Ruffels stormed home with four birdies to fire a warning signal.
It was a great day overall for the Australian contingent with Karis Davidson, Grace Kim and Robyn Choi all shooting 66.
World No.5 Minjee Lee and fellow Western Australian Hira Naveed are a further two shots behind and also in contention.
But the player they will all be wary of is Nelly Korda, who shot a 6-under 66.
The top-ranked Korda opened with four birdies in five holes and closed with a two-putt birdie on the par-5 18th as she tries to become the first LPGA Tour player to win three straight starts since Ariya Jutanugarn in 2016.
Korda won the Drive On Championship in her hometown of Bradenton, Florida, before sitting out all of the LPGA Tour's Asian swing. She showed no rust after the long break, winning last week to move back atop the world ranking.
"Completely different today compared to last weekend," Korda said. "The greens are quite soft. I know Arizona has been getting a good bit of rain throughout the winter. I knew there would be low scores out there, so needed to be aggressive."
Anannarukan took advantage with a bogey-free, 9-under 63 after starting on the back nine at the 6,734-yard course in suburban Phoenix.
She enjoys a one-shot lead over Ruffels, Lilia Vu, Isa Gabsa, Azahara Munoz and Carlota Ciganda.
Anannarukan has won twice on the LPGA Tour, including last year's Bank of Hope Match Play. The 24-year-old from Thailand closed with five straight birdies to shoot 6-under 30 on Seville's front nine.
Vu fell out of the top spot in the world when Korda won in a playoff last week at Palos Verdes Golf Club. The two-time major champion sandwiched four birdies around a bogey on the par-3 eighth and had four birdies on the back nine.
Ciganda rolled in eight birdies in a bogey-free round that started on the back nine. Munoz had a wild round that included eight birdies, an eagle and two bogeys in her bid to win for the first time since the 2012 Sybase Match Play Championship.
Gabsa had three birdies on the front nine, then reeled off four straight to shoot 5-under 31 on the back to finish off her bogey-free round.
Celine Boutier and Hyo Joo Kim shot 65.
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