It will be world number one against fourth seed but there is no doubt it is the latter who is the favourite to win a fourth US Open title and a 15th grand slam singles crown.
Williams swatted aside Italy's Sara Errani 6-1 6-2 in the semi-finals and has dropped only 19 games on her way to the final.
The American also has the advantage of having won nine of her 10 previous meetings with Azarenka, who edged a much tighter contest against Maria Sharapova 3-6 6-2 6-4.
The last time Williams and Azarenka met, in the semi-finals of the Olympics last month, the world number one managed only three games as Williams went on to add gold to her Wimbledon crown.
Azarenka said: "She's the toughest opponent there is in the draw, and being in the final makes it even more difficult.
"If you look at our record - it says it all. I haven't won in any of the last (seven) meetings, so I definitely need to find something to surprise her, because she's in great form and feeling really confident right now. She has everything on her side."
Williams simply overpowered the diminutive Errani, hitting 38 winners to six, and is now hoping - whatever the outcome of the final - that it plays out in a different fashion to last year's final against Sam Stosur.
Williams was penalised for yelling out during a point and got into a furious row with umpire Eva Asderaki, for which she was later fined.
It was Williams' second major controversy at Flushing Meadows after her infamous abuse of a lineswoman in her 2009 semi-final against Kim Clijsters.
The 30-year-old said wryly: "My goal this year was not to get in any fights. Hopefully I can make it. I grunted once today [Friday] and I thought, 'I hope I don't lose the point'. There's still one match to go."
Williams, meanwhile, insisted she will not feel like the favourite heading into the match, saying: "I don't feel I have anything to lose.
"I'm going up against I think the most consistent player this year. I always believe I'm the best, but she's been more consistent than I have, going deeper in the slams."
Errani had few words of encouragement for Azarenka, saying of Williams: "The way she wants to win, when she play like this, I think she's best player in the world. Azarenka is also a strong player but I think Serena is on another level."
Azarenka had lost only three games to Sharapova in the Australian Open final in January, winning her first grand slam title, but this was a lot tougher.
The Russian dominated the first set and broke serve at the start of the second before her radar went slightly off kilter and Azarenka began to find her range.
The deciding set lasted 74 minutes but the pressure was always coming from the Belarusian and Sharapova could resist no longer when she served to stay in the match.
Azarenka said: "I felt like towards the end of the first I was getting a little bit better, trying to find the momentum and getting more and more comfortable in the match.
"So even though I lost the first set, I felt like it was close. I had a few opportunities - I missed them. But, once it finished, I thought that I had to turn it around and start from zero."
Sharapova viewed the match as a missed opportunity and felt her failure to push Azarenka harder in the deciding set cost her.
She said: "It's frustrating, but it's the game of tennis. There were a lot of swings in the match. I certainly had the lead and the advantage.
"She picked up her game. In the third I think a lot of it had to do with the returns. I didn't do much on her service games. She was winning them pretty easy.
"On mine they were quite long and I was just making too many errors and not putting any pressure on her. So I think that's the most frustrating part."
It has still been a terrific season for Sharapova at the grand slams, with the Russian returning to the winners' circle for the first time in four and a half years at the French Open in June.
After the shoulder problems that almost ended her career, it was a particularly satisfying moment, and Sharapova said with a smile: "I'll take the results I had this year.
"I look back at the beginning of the season and I remember going to Australia early and not really being sure I was going to play the warm-up tournament because my ankle was still not feeling great.
"So if anyone had told me then that I would have this type of season, and it's still not over, I would have been pretty happy."