The 33-year-old, two victories from winning the first calendar Slam since 1988, plays Roberta Vinci in Friday’s delayed US Open semi-finals.
The first semi-final is between Simona Halep and Flavia Pennetta at 16:00 BST.
“She’s the greatest female player I’ve ever seen,” McEnroe told BBC Sport. “She’s proven it to me over and over.”
The men’s semi-finals will get under way at 22:00, with Novak Djokovic against Marin Cilic followed by Roger Federer against Stan Wawrinka, but it has been Williams in the spotlight throughout the tournament.
The world number one currently holds all four Grand Slam titles, and another victory in New York would take her to 22 majors.
That would match the total of Germany’s Steffi Graf, the last player – man or woman – to win all four Grand Slams in the same season, 27 years ago.
“I think Serena is one of the all-time greatest athletes, period. Man or woman,” added McEnroe, a former world number one and four-time US Open winner.
“You’re looking at an incredible athlete and we’ve got to enjoy this last year or two that we have her around, because there’s going to be a huge void when she’s gone.”
Tickets for the women’s final at Flushing Meadows sold out quicker than for the men’s showpiece for the first time, while Williams’s pursuit of the calendar Slam has helped increase TV viewing figures.
“It was a boost for the US Open in general,” said McEnroe.
“Obviously for women’s tennis it helps a great deal because without Serena, where would they be right now?
“I bet you 98% of people in the States couldn’t tell you who the other three semi-finalists are.”