Venus, who also won the title in 2000, is on the comeback trail after withdrawing from the US Open ahead of her second-round match a year ago with an autoimmune disease.
Younger sister Serena will also be in action at the National Tennis Center on Thursday when the fourth seed and three-times champion faces Spain's Maria Jose Martinez Sanchez in a second-round match.
On the men's side, world number one Roger Federer, gunning for his sixth title at Flushing Meadows, will take on Germany's Bjorn Phau, ranked 83rd, in a second-round affair.
Venus, formerly the top-ranked player in the world, is convinced she can make the climb back into the top 10 despite tumbling to her current spot at 46.
"I'm looking forward to the top 10, all that great stuff," said the 32-year-old, seven-times Grand Slam winner. "I feel like I have it in me."
Venus beat Bethanie Mattek-Sands 6-3 6-1 in her first-round match, while Kerber routed Britain's Anne Keothavong 6-2 6-0.
In other matches, 12th seed Ana Ivanovic, also a former top-ranked player, takes on Sofia Arvidsson of Sweden while, on the men's side, fifth seed Jo-Wilfried Tsonga of France battles Slovakian Martin Klizan, ranked 50th.
The 31-year-old Federer, who lost to Serbian Novak Djokovic in the US Open semi-finals last year, said he enjoys New York but it may not be too good for his tennis game.
"The distractions are big here just because you almost enjoy your time too much," the Swiss said. "Not meaning you go party, but you do too many things maybe you shouldn't be doing.
"Maybe when you come on court your mind is still elsewhere, those kinds of things. Whereas in Wimbledon, you rent your house, you're full on tennis. All you do is you watch tennis. You eat and breathe tennis.
"When you come here, you go out at night for dinners. You catch up with friends. You do maybe watch things on TV from time to time. There's many more things you can follow and do, so that brings challenges automatically with it."