The Wimbledon champion pairing were nominally the underdogs against their sixth-seeded opponents but wrapped up a comfortable 6-3 6-2 victory inside an hour on Rod Laver Arena.
It was a third Melbourne Park mixed doubles title for Canadian Nestor after his 2007 triumph with Elena Likhovtseva and 2011 victory with Katarina Srebotnik.
Nestor then told his 20-year-old partner Mladenovic on court that he would now like to target a sweep of the major titles to complete the grand slam in one year.
"I was half joking but I always tell my friends my best chance of winning grand slams nowadays are in mixed," the 41-year-old, who now has won a total of 12 grand slam doubles titles, later told reporters.
"But obviously I'd still like to win men's doubles titles, too... I just think this is the best chance, but I'll keep playing both and hopefully good will come out of it."
The last time a single partnership won doubles titles at all four majors in one year was when Martina Navratilova and Pam Shriver performed the feat in women's doubles in 1984.
Defeat for Indian Mirza and her Romanian partner Tecau denied Asia a second Australian Open champion in two days after China's Li Na won the women's singles title on Saturday evening.
"I've had a good week in the mixed so it's a good start to the year," said Mirza, who no longer plays singles.
(Reporting by Nick Mulvenney; Editing by John O'Brien)
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