Kyrgios, the world number 40, said his decision "hurts me at my core" and criticised some of his fellow players in a video posted on social media.
World number one Novak Djokovic faced a fierce backlash in June after he tested positive for Covid-19, days after hosting a number of players in the Adria Tour exhibition tournament.
Djokovic was criticised for putting the tournament on during a pandemic after Grigor Dimitrov, Borna Coric and Viktor Troicki also returned positive tests after playing at the event in Serbia and Croatia,
Kyrgios, who previously called the decision to proceed with the tournament "boneheaded", accused Djokovic at the time of "taking the cake" while sharing a video of the Serb out dancing with fellow players before his positive test.
Following Kyrgios' decision not to play at the US Open, the Australian said: "I've got no problem with the USTA putting on the US Open and if players want to go, that's up to them so long as everyone acts appropriately and acts safely.
"But tennis players, you have to act in the interests of each other and work together.
"You can't be dancing on tables, money-grabbing your way around Europe or trying to make a quick buck hosting the next exhibition. That's just so selfish.
"Think of the other people for once. That's what this virus is about. It doesn't care about your world ranking or how much money you have. Act responsibly."
The US Open is scheduled to start behind closed doors at Flushing Meadow on August 31.
Fellow Australian Ashleigh Barty, the current women's world number one, withdrew from the tournament earlier this week and Andy Murray said he expected more players to follow.
Reading an open letter on his video, Kyrgios said the global economy and tennis could rebuild, "but we can never recover lives lost".
"Dear Tennis, let us take a breath here and remember what is important, which is health and safety as a community," Kyrgios said.
"To those players that have been observing the rules and acting selflessly, I say good luck to you. Play at your own risk - and I have no problem with that.
"I will not be playing this year at the US Open. It hurts me at my core not to be out there competing at one of the sports' greatest arenas, Arthur Ashe Stadium.
"But I'm sitting out for the people, for my Aussies, for the hundreds and thousands of Americans who have lost their lives. For all of you."