The new combination had to battle from a set down to defeat Belgian Kirsten Flipkens and Frenchman Edouard Roger-Vasselin 4-6 6-4 [10-7] in Saturday's high-quality final in New York.
Their triumph continued the excellent series of Australian successes in grand slam doubles in 2022, which also featured the men's wins at the Australian Open (Thanasi Kokkinakis and Nick Kyrgios) and Wimbledon (Max Purcell and Matt Ebden).
It was Queenslander Sanders' first grand slam victory while the 34-year-old Peers again demonstrated his long-standing doubles prowess in the Arthur Ashe Stadium as he added the title to his 2017 Australian Open men's victory.
The fourth seeds showed their mettle in a fluctuating contest, notably producing their best tennis both at the start of the match and in the 10-point tiebreak decider.
And their unstoppable finish saw them become the first all-Australian mixed doubles champs at Flushing Meadows since Rennae Stubbs and Todd Woodbridge captured the 2001 title, while they also could celebrate a cool $US163,000 ($A238,000) payday.
"I can't believe we're grand slam champions," beamed the 28-year-old Sanders, the Queensland left-hander who hails from Rockhampton, the town that produced the best southpaw of all, Rod Laver.
Turning to Peers, Sanders, who also reached the women's doubles semis, told him: "It's crazy - thanks so much for playing with me ... To play on the biggest court in the world, it's been a memorable experience."
For Melbourne's Peers, it was particularly sweet as he finally won a mixed doubles grand slam title at the 32nd time of asking, having delivered the winning ace in the tiebreak in front of watching wife and two daughters.
"Stormy, we got one! Well done!" he told Sanders.
Both had also been inspired by the presence at courtside of Australian Samantha Stosur, the 2011 US Open singles winner. "It's a pleasure to play in front of a champion like you," Sanders told her.
Stosur, along with Ebden, had already been knocked out in the quarter-finals at Flushing Meadows by Flipkens and Roger-Vasselin but Sanders, quite brilliant at the start, and Peers looked in no mood for a repeat as they raced into a 3-0 lead.
But having dropped only one set all tournament, the first all-Australian team to reach a US Open mixed doubles final since Alicia Molik and Woodbridge in 2004, lost their way and fell a break down at 3-4.
Down a set, Peers, brilliant all match with his overheads, upped his game when it mattered most, producing the goods for the key break - and their only one - in the 10th game of the second stanza.
They then just about controlled the breaker thanks to the buffer of an early 3-0 lead.
"I trusted Johnny on his serves and volleys," Sanders said, recalling how she hoped "he can hit a good serve on match point."
He did just that - with his ace down the T.
The Australian pair, old friends, had been hoping to play a tournament together for some time but it had never worked out, until they arranged this year to play at Flushing Meadows.
"We'll be back next year," Sanders promised the crowd, beaming, before Peers later insisted that before that, they'd be in action together in Melbourne.
"We're definitely playing Aussie," he smiled.
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