The American-Czech pairing battled past 12th-seeded Andrea Hlavackova, also from the Czech Republic, and China's Peng Shuai 6-7 (4/7), 6-3, 6-3 on Rod Laver Arena.
Mattek-Sands and Safarova got the decisive break in the fourth game of the deciding set to go 3-1 up after Hlavackova sent down a double fault.
There was no looking back, with Mattek-Sands clinching the title with a volley as they jumped for joy and then celebrated with a dance routine in front of the trophy.
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