The showdown will be between the greatest player of her generation and the current world number one.
Williams was at her ruthless best as she demolished Italian Sara Errani 6-1 6-2 to continue her golden summer while Azarenka was no less impressive as she clawed her way out of trouble to beat Maria Sharapova 3-6 6-2 6-4 at Flushing Meadows.
With momentum on her side after winning a fifth Wimbledon title in July then the Olympic singles and doubles events at the London Games, Williams will start Saturday's final as the overwhelming favourite.
"I think it will probably be the best summer I've ever had," she said.
"It will be up there because if you win the Olympics and Wimbledon and this, it would be kinda cool."
Few players have ever been able to keep pace with Williams when she is fit and in form and Azarenka knows the enormity of the challenge she faces.
The Belarusian has been the most consistent player in the world this year and won her first grand slam title at the Australian Open in January but her previous results against Williams have been poor, with the American winning nine of their 10 clashes.
"She's the toughest opponent there is in the draw," said Azarenka. "And being in the final makes it even more difficult so it's definitely gonna be a tough one."
Despite the hurdles she faces, Azarenka is not without hope. The 23-year-old is a player on the rise with plenty of big weapons and nerves like steel.
She beat the defending champion Sam Stosur in a deciding third set tiebreak to make the semis then came from a set and a service break down to defeat Sharapova, who won the French Open in June to complete her collection of grand slam titles.
The Russian dominated most of the match but paid the price for her aggressive approach. She hit 44 winners and eight aces, but the flipside was her 42 unforced errors and 10 double faults, a recurring problem she has had for years.
"I gave her too many free points," Sharapova said. "When I had my opportunities I don't think I took them."
Sharapova, one of just three women to beat Williams in a grand slam final, did however offer some words of encourgament to Azarenka.
"No matter who is going in there as the favourite, no matter how confident they are, everyone has a chance," Sharapova said.
"She's number one in the world and there is no reason why she shouldn't have a chance."
Even so, the odds are still heavily stacked in favour of Williams, who already has 14 grand slam titles, including three from the US Open.
She has not dropped a single set on her way to the final and has got better and better with each match, giving Errani, runner-up at the French Open this year, little chance.
"I think she is incredible," the Italian said. "When she plays like this, I think she's the best player in the world."
Williams won her first US Open title in 1999 when she was just 17 but is now bidding to become the oldest woman to win since Margaret Court triumphed, aged 31, in 1973. Williams turns 31 later this month.
"I feel a lot of support here," she said. "And being the last American, both the men and the women, it's exciting. You want to see your country do well.
Williams was beaten by Stosur in last year's final just months after she was diagnosed with a life-threatening blood clot in one of her lungs but says she is in better shape, physically and mentally, this time around.
"I know it sounds weird but I have more experience than I did last year," she said.
"I feel like I'm going up against the most consistent and the best player this year, being Victoria Azarenka.
"I feel like I don't have anything to lose, and it will be a good challenge for me." – Reuters