McEnroe, who made a career out of his outlandish on-court antics during the 70s and 80s, blasted Kyrgios throughout the 7-5 6-3 4-6 6-1 loss.
Krygios has a suspended 28-day ban and fine hanging over his head for his 'Kokkinakis banged your girlfriend' sledge to Stan Wawrinka last month - but it was business as usual for the enigmatic 20-year-old in front of a packed house at Arthur Ashe Stadium.
He appeared to fall asleep during one of the changeovers, smashed his racket, talked to himself constantly and launched a lengthy rant at umpire Carlos Ramos for allowing fans to enter the stadium during one of his service games.
In between Kyrgios showcased his undoubted talent with a sprinkling of breathtaking shots, but his between-the-legs half-volley as he pressed to try to break Murray's serve in the second set four-time US Open champion McEnroe off during his commentary stint on ESPN
"An absolute brain freeze. Absolute stupidity. He could have volleyed that away for another break-point chance," a bemused McEnroe said.
"I hope he learns from these bonehead moves. He should be a seed already, at least 20. You don't want to be remembered as a clown. You want to be remembered as a player.
"So he better step up. Otherwise he won't be talked about too much. He thinks he's a vaudeville entertainer. I don't know what's going on here."
Kyrgios recently turned to former world No.1 Lleyton Hewitt to mentor him and McEnroe last week offered to help the world number 37.
"I think he could achieve winning Grand Slams, could be like one of the top players in the world," he said.
"I think that's what he could achieve. Hopefully he'll get some better advice. I'd be happy to give him some and be supportive of this."
But the task of taming Kyrgios could prove to be Mission Impossible.