Seven-time grand slam winner McEnroe reopened an age-old debate by telling US radio network NPR that Williams would "be like 700 in the world" if she played on the men's Tour.
Williams, winner of 23 grand slam singles titles and the only woman in Forbes' list of the world's 100 highest-paid athletes in 2017, announced in April she was expecting her first child.
Reacting to McEnroe's comments, the 35-year-old tweeted: "Dear John, I adore and respect you but please please keep me out of your statements that are not factually based.
"I've never played anyone ranked 'there' nor do I have time. Respect me and my privacy as I'm trying to have a baby. Good day sir."
'Serena's an incredible player'
McEnroe, 58, emphasized that Williams was "an incredible player" and the "best female player ever -- no question."
Neither did he rule out that a female player would one day be able to outshine the world's best male players, saying: "Maybe at some point a women's tennis player can be better than anybody.
"I just haven't seen it in any other sport, and I haven't seen it in tennis. I suppose anything's possible at some stage."
Ranked 700 in the world on the men's Tour is Issam Haitham Taweel of Egypt, a 27-year-old with no career titles, while Russia's Dmitry Tursunov is a place below him in the rankings.
Tursunov, 34, told the BBC that he hoped that he would beat Williams were they to ever play each other.
"It would be a similar argument to: who would run faster, the fastest woman or the fastest man? Tennis is becoming more and more a physical sport, so it's going to be hard for a woman to beat the men," said the former world No. 20, who has won seven career titles.
"It's not black and white, there are lots of factors to take into account. Physically I might not be in the best shape of my life, but as an overall package I'm much better than my ranking would suggest. She is pregnant, and I'm not.
"I've never heard John say anything absolutely stupid -- he knows his stuff. What he said about her being an incredible player is correct -- explosive, powerful and she puts in a lot of work. But I would hope that I would win."
Williams, one of the greatest athletes of her generation, has said she will make her tennis comeback next year.