Isner says he is happy to chase medals on three fronts - singles, doubles and mixed - at London 2012 this summer and feels friend Serena would be his ideal partner for the latter competition.
Mixed doubles is being played at the Olympics for the first time since 1924 this year and the draw is promising to produce some stellar pairings.
With Isner one of the biggest servers in the men's game and Williams one of the most ferocious hitters on the women's side, the duo would make a formidable team on the slick grass of Wimbledon, where the Olympics will be played in July and August.
Isner, who replaced Mardy Fish as the top US player on Monday following his run to the final in Houston, said: "It's going to be a very hectic schedule at the Olympic Games this year, but I'm planning on playing singles and men's doubles and would like to play mixed also.
"It's a lot of tennis in a short amount of time but it's a surface I can do well on.
"Serena or Venus Williams would be an ideal partner for the mixed."
When pushed on the subject, Isner, who has beaten both Novak Djokovic and Roger Federer this season, added: "(Me and Serena) have kind of joked about it. Andy Roddick wants to play with them, one of the Bryan brothers wants to play with them.
"I'm good friends with Serena - I might bribe her, send her a gift in the mail!
"She's one of the most dominant players of all time. To have her on my team would be a big advantage."
The USA will be restricted to a maximum of two pairs in the mixed doubles field of 16. Combined singles and doubles rankings will be used to determine who is eligible but Isner is well set to make the cut having a singles ranking of nine and a doubles ranking of 30 at present.
Final entries for the mixed event will not be known until July 31, by which stage the singles and doubles will already be under way.
British star Andy Murray recently admitted he is considering entering all three events. Such is the schedule that players who compete in all three face the prospect of playing three matches in one day on August 2.