The seven-time Grand Slam champion said Williams was "the best female player ever" but against men it would be an "entirely different story".
Williams, a 23-time Grand Slam champion, responded to McEnroe, asking him to "respect me and my privacy".
McEnroe, 58, said: "I've got a solution. Men and women play together."
"Then we don't have to guess," added the American. "I'm sure the men would be all for it."
Dmitry Tursunov - the male player ranked 701 in the world - also said on Tuesday he believes he could beat American Williams, who is due to give birth in autumn.
"I would hope that I would win against Serena," he told BBC World Service Sport.
The 34-year-old Russian, once ranked as high as 20th in the world, said he did not think McEnroe was "trying to talk women's tennis down" but said "the reality" was that "men are stronger in general".
"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.
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Williams, 35, who is the most successful female player of the Open era, confirmed her pregnancy in April, just 12 weeks after winning her record 23rd Grand Slam singles title.
"Dear John, I adore and respect you but please please keep me out of your statements that are not factually based," said Williams on Twitter.
"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."
The world number two expects to be back on court as early as January 2018.
Tennis matches between men and women have occurred before, mostly notably back in 1973 when Billie Jean King took on fellow American Bobby Riggs.
Riggs, the world number one in the 1940s, retired in 1951 and at the age of 55 believed he could beat any of the top female players.
King originally declined to play Riggs and Australian Margaret Court - at the time the top female player in the world - stepped in. Riggs won 6-2 6-1.
But later that year, the top-ranked women's player King - 26 years younger than Riggs at 29 - took him on in an exhibition match at the Houston Astrodome and won 6-4 6-3 6-3.
A third 'battle of the sexes' match took place in 1992 between American former world number one Jimmy Connors, aged 40 at the time, and Czech/American Martina Navratilova, who was 35.
The match took place under special rules to make it more competitive - Connors was allowed only one serve per point, and Navratilova was allowed to hit into half the doubles court. Connors won 7-5 6-2.

Donal Hassett, 57, was accused of acting as the property fixer using fake paperwork to rent four homes which were later turned into cannabis factories.
He was convicted at Bristol Crown Court on Wednesday of conspiring to produce cannabis.
The prosecution described their drugs operation as an "organised, sophisticated drugs syndicate".
Cannabis was produced between January 2015 and March 2016 in four properties across the West Country, the court heard.
Hassett, of Southdown Road, Bath, was suspended from the Conservative Party when he was charged. He is currently an independent councillor.
Conservative leader Tim Warren said in a statement on Wednesday that "the party, and he personally, felt very let down by Donal Hassett".
A council spokesman said: "The council takes this matter extremely seriously.
"We expect the highest standards from all our members and Cllr Hassett's behaviour falls far short of this."
Hassett was remanded in custody until sentencing.
Six others, five men and woman are due to be sentenced for their part in the drugs ring.
John McEnroe has proposed a men v women contest to prove his claim that Serena Williams would be ranked "700 in the world" on the men's circuit.
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A Bath councillor has been found guilty of being involved in a cannabis drugs ring.