The British-American duo's victory at Rod Laver Arena gave Harrison his first Grand Slam title and marked Skupski's fourth in doubles and mixed doubles, though his first outside Wimbledon.
The partnership is remarkably fresh, as the pair started playing together only two weeks ago in Adelaide after training for a week together in Baton Rouge in December.
Skupski silences raucous home fans
"We obviously started playing together in Adelaide two weeks ago now," Skupski said.
"We didn't know obviously how it would go. It seems to be going pretty well so far!"
With the roof closed at Rod Laver Arena due to the rain, the match began at a fast pace under the lights and proved to be an entertaining affair, as the opening set went with serve until Harrison and Skupski broke for a 4-2 lead.
But with the raucous Australian fans firmly behind them, Kubler and Polmans - wearing his trademark legionnaire hat - broke Harrison's serve and consolidated it to level the set at 5-5 before forcing a tiebreak.
They were neck-and-neck in the tiebreak at 4-4 until the British-American duo inched ahead and took the opening set when Skupski smashed an emphatic overhead shot at the net to silence the home fans.
In the second set, Harrison and Skupski broke Polmans' serve early for a 3-1 advantage and they did not look back despite a determined fightback from the Australian pair.
Another Grand Slam win for Harrison household
They made it 5-3 on Skupski's serve when Harrison smashed a volley at the net to put the pressure back on the Australians, who managed to keep them at bay by saving a championship point on serve.
But Harrison proved indomitable at the baseline on his own serve as they served for the title.
Although they failed to convert another championship point, they sealed the title at the third time of asking when the American fired an ace down the middle.
The victory brings another Grand Slam trophy into the Harrison household after his elder brother Ryan, also his coach, won the French Open doubles title in 2017.
"My parents are back home, and I remember I was with them when I watched my brother win the French Open on TV and they were emotional wrecks. So I know they're probably doing the same right now," Harrison said.
"Thanks to my partner, without you it's not possible. I was so excited to just get on the court with you. In some tight moments, I knew your experience was going to help pay off in the end and it did. It was fun to battle in this match together."