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The 97th-ranked Sandgren defeated ninth seeded Wawrinka 6-2, 6-1, 6-4 and will next play Germany's Maximilian Marterer.
It has been tough so far this year for Wawrinka, who was playing in his first tournament since Wimbledon six months ago following left knee surgery.
He was never in the contest and had his serve broken five times and made only 21 winners and 35 unforced errors.
The three-time Grand Slam winner, who defeated Rafael Nadal to win the 2014 Australian Open, has slipped to nine in the world rankings and faces a battle to climb higher after his early round exit.
He made the semifinals at last year's Australian Open where he lost to eventual champion Roger Federer in five sets.
Wawrinka had a troubled lead-in to the year's opening Grand Slam, pulling out of an exhibition event in Abu Dhabi on his way to Australia.
He has not played a competitive match prior to his first round Open win over Lithuania's Ricardas Berankis, having only decided to take part last weekend.
Sandgren's next opponent, world No.94 Marterer, reached the third round with a 6-4, 4-6, 7-6(5), 3-6, 6-3 over Spanish veteran Fernando Verdasco.
Defending champion Roger Federer needed to knuckle down to end the feisty challenge of hard-hitting German Jan-Lennard Struff with a 6-4 6-4 7-6(4) win in the second round.
Federer coasted through the opening sets under the lights at Rod Laver Arena but was dragged into a scrap in the third as the 55th-ranked Struff broke his serve and took the match into a tiebreak on a steamy night.
Federer will meet French 29th seed Richard Gasquet for a place in the last 16 as he continues his bid for a 20th grand slam title.
Meanwhile, Novak Djokovic says the furnace conditions at the Australian Open were right on the limit as he won a survival of the fittest battle with Gael Monfils to reach the third round.
The six-time champion staggered over the finish line to stretch his unbeaten record over Monfils to 15-0, one of the longest at Tour level, after dropping the opening set.
Djokovic, playing in his first tournament for six months after an elbow injury, just did enough at the end to carve out a 4-6, 6-3, 6-1, 6-3 win in 2hr 45min on baking Rod Laver Arena.
The 12-time Grand Slam champion has a day to recover for his third round encounter with Spanish 21st seed Albert Ramos-Vinolas.
Playing conditions were described as brutal as temperatures hovered around 40 Celsius (104 Fahrenheit), prompting Djokovic to say a safety limit had been reached for the players.
"People might say at this level you have to be as a professional tennis player fit," Djokovic said.
"It's the beginning of the season. You work and train hard to be able to sustain these kind of conditions, to be tough.
"But I think there is a limit, and that is a level of tolerance between being fit and being, I think, in danger in terms of health. It was right at the limit."
The extreme elements made it a desperate struggle just to finish the match with Monfils looking the worse for wear early before Djokovic had enough in the tank to win on his fourth match point in a gruelling eight-minute final game.
"It was brutal conditions and we both suffered, it was a big challenge for both of us," Djokovic said.
"Gael is one of the best athletes in our sport but he was not at his best in the second and third sets. It was about just hanging in there and try to use every opportunity."
Asked about the state of his right elbow, Djokovic added: "It's still not 100 percent, but it's building. I have a lot of faith and belief in what I am capable of."
It was another step forward for the Serbian former world number one, who has been working his way back with a remodelled serve after elbow problems.
A decade after winning his first Melbourne Park title Djokovic has slipped to 14 in the world, his lowest in 10 years, but he has survived the opening two rounds in his comeback Grand Slam.
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