In a tit for tat battle, where service holds were at a premium, the Williamses eventually saw off the stubborn resistance of their compatriots, 64 64.
Their reward is another test against one of the WTA's more established pairings, Anastasia Pavlyuchenkova and Lucie Safarova, who won a hard-fought encounter against wildcards Jill Craybas and CoCo Vandeweghe, 76(6) 64.
For Craybas, defeat brought down the curtain on a 17-year professional career that saw her pick up one singles and five doubles titles. After recovering from a set and a break down in their first round, it looked like Craybas and Vandeweghe could be inspired to pull off another improbable victory, but it was not to be.
"Even just walking out onto the court, I started to get a little sad thinking this could be my last match," she said. "We lost the first set pretty badly on Friday and I was like, 'Oh my God. Really?' But then I was able to relax a little bit more and then the crowd really started getting into it, so it became exciting.
"The US Open has always been my favorite tournament. New Yorkers love their sports and they bring that energy to the site, so it's been amazing to play here all these years."
Craybas, who has dabbled in some radio work during the US Open, is still unsure of her plans for retirement, but is certain that she is not waving goodbye to the tennis world for good. "You look at some players when they retire and they never want to see a tennis court again in their lives. I'm so happy that I'm not ending my career that way," Craybas added. "I still love playing and still love the game."
Elsewhere, there was better news for another stalwart of the American game, Lisa Raymond, who alongside partner Polona Hercog, booked a spot in the third round with a 57 64 75 win over No.12 seeds Julia Goerges and Barbora Zahlavova Strycova.