"Somewhat inexplicably for a guy that serves as big as Isner, he's really had very poor results," American McEnroe said of the towering world number 10, who has never advanced past the tournament's third round.
"But he's got about as good a draw as I've seem him have."
Isner will first face German world number 134 Yannick Maden and then either countryman Steve Johnson or Belgian Ruben Bemelmans with 20th-seeded Spaniard Pablo Carreno Busta lurking as a possible third-round opponent.
Isner showed he is more than just his blazing serve en route to his first Miami Open title in April but was knocked out of the French Open in the round of 16 by fellow power-hitter Juan Martin Del Potro in straight sets.
"His movement and his return of serve have been issues but he's got about as good an opportunity to make a run as he ever has," McEnroe said.
The 11th-seeded Querrey, who defeated twice champion Andy Murray on his way to the Wimbledon semi-finals last year, is riding a wave of confidence heading into what he calls his favourite tournament.
YOUNG GUN
Querrey advanced to the quarter-finals of the Queen's Club Championship this month and defeated Australian young gun Nick Kyrgios in straight sets at The Boodles this week.
But McEnroe, 59, said the hard-hitting Californian will struggle to advance as far as he did last year given his draw, where he could face top seed Roger Federer in the quarter-finals.
"Sam is the most confident and plays the best on grass but he has what I see as the toughest draw of any American," McEnroe said.
"He's got to go through some pretty solid grass court players to even get where he was last year."
And while the veterans face an uphill battle, it is probably too early to expect a breakthrough by any of the next generation of American men.
"The young guys still have a ways to go in terms of figuring out what they can do to max out their game," McEnroe said, referring to 20-year-old Frances Tiafoe and 21-year-old Jared Donaldson.
"We're still a work in progress with the young guys."
The biggest question mark of the group is baseline specialist Jack Sock, who reached a career-high ranking of world number eight at the end of last year but has struggled in 2018, posting a 5-12 record.
Sock has lost his opener in his last three majors including an ugly first-round defeat by French Open lucky loser Jurgen Zopp in a match that included an outburst from the 25-year-old at the chair umpire.
"He hasn't been playing with really any confidence in a while and I'm not quite sure what's happened with him," McEnroe said.
"Even though I think he could play on grass and do well, I haven't seen any indication from him that he believes he has much of a shot either at this point."
Pete Sampras was the last American man to win Wimbledon, claiming his seventh title at the All England Club in 2000. Andy Roddick finished runner-up in 2004, 2005 and 2009.
Wimbledon runs from July 2-15.
(Reporting by Rory Carroll in Los Angeles, editing by Ed Osmond)
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