This is not the first time Kyrgios has been booed off court in the United States, with the Australian suffering similar abuse this time last season when he retired hurt from the Washington Open when a set and 0-3 down to American Tennys Sandgren.
On the other side, Kyrgios and partner Jeremy Chardy are set to clash against USA's Denis Kudla and Frances Tiafoe in the doubles first round.
He was losing the match 7-5, 3-0 when he ultimately made a decision to call it quits.
The Aussie had been his flamboyant self in the match, doing some on-court impersonations to keep the crowd happy.
Kyrgios was also fined $US10,000 for walking off court in the Shanghai Masters in 2017, later citing stomach problems and an injured shoulder as the reason for his abrupt exit.
"I was struggling a little bit", Isner, a four-times champion in Atlanta, said.
"He's so talented. Who knows what he could do in tennis if he was healthy?" "I know a lot about him". "I need to get in the air conditioning and just rest so I could be ready for tomorrow".
A day earlier, Kyrgios had pumped up his chances following a cruisy 7-5 6-2 win over American Noah Rubin.
"I always feel comfortable playing here. the court suits my game style", he said yesterday.
Despite the retirement, the usual hot takes were pointed squarely at the Aussie's perceived lack of effort.
Matt Ebden will fly the Australian flag in the last four after he required just 71 minutes to defeat Marcos Baghdatis.
After seeing the trainer in the first set, Kyrgios then went 3-0 down to the 22-year-old Briton in the second before deciding to pull out of the match, prompting a chorus of boos from the crowd.
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