It was the first grand slam title for the unseeded Pavic and Siegemund, who swept through all 10 sets and three tie-breaks to hoist the trophy.
Siegemund, seeded 26th in the women's singles at the U.S. Open, lost to Venus Williams in the third round.
Highlights: Pavic and Siegemund beat Ram and Vandeweghe to mixed doubles crown
The U.S. Open also marked the first time that Vandeweghe and Ram, who won a silver medal with Venus Williams at the Rio Olympics, had teamed up.
It was further grand slam disappointment for Vandeweghe, who lost in the final of this year's Australian Open mixed doubles with Horia Tecau.
Mate Pavic and Laura Siegemund - 2016 US Open Mixed Doubles champions
Image credit: AFP