Serena has been in dominant form at the Games as she chases a first singles gold medal and Belarus's Azarenka was no match for the imperious American fourth seed, who cruised to victory in just 63 minutes on Wimbledon's Centre Court.
Williams, who hit 33 winners and 16 aces, is now guaranteed at least a silver medal, but both she and Sharapova will be hoping to complete a Golden Slam of titles in all four majors and the Olympics singles.
The 14-time Grand Slam champion will be the favourite against Sharapova after winning eight of their 10 meetings, including the last seven.
But the Russian world number three famously beat Serena to win the 2004 Wimbledon final aged just 17.
Serena, twice a doubles gold medallist with sister Venus, had hammered down 24 aces in a straight-sets Wimbledon semi-final win over Azarenka last month and, ominiously for the Belarusian, Williams has been in even more formidable mood over the last week.
She hasn't lost a set and has dropped only 16 games en route to her first Olympics singles finals.
Azarenka, the reigning Australian Open champion, has been enjoying her best year on the women's tour, but she must have feared this would be a chastening experience from the moment Serena broke in the second game of the first set.
Once again Serena was producing winners from all angles and her power was simply too much for Azarenka, who was broken twice more in the first set.
When Williams broke again in the first game of the second set, it was only matter time before the American reached the finish line and she didn't hang around, breaking twice more to complete another ruthless demolition.