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Kyrgios follows compatriot and women's world number one Ash Barty, who withdrew from the August 31-September 13 tournament earlier this week.
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"I will not be playing this year at the U.S. Open," Kyrgios said in a video on social media on Sunday.
"It hurts me at my core not to be out there competing in one of the sport's greatest arenas, Arthur Ashe Stadium.
But I'm sitting out for the people, for my Aussies, for the hundreds and thousands of Americans that have lost their lives, for all of you. It's my decision.
Kyrgios had no problems with the USTA scheduling the tournament or players competing if they chose, "so long as everyone acts appropriately and acts safely".
The 25-year-old said he recognised that lower-wage employees at the event, such as restaurant staff, cleaners and locker room attendants, needed the tournament to take place.
The world number 40, however, also took another shot at some of his fellow players, with whom he has been involved in a running battle over the last two months after they chose to play in a Novak Djokovic-organised exhibition event in Europe.
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Djokovic, Borna Coric, Grigor Dimitrov and Victor Troicki all tested positive for Covid-19 during the event, which was hastily cancelled.
"Tennis players, you have to act in the interest of each other and work together," Kyrgios added.
"You can't be dancing on tables, money grabbing your way around Europe or trying to make a quick buck hosting an exhibition. That's just so selfish.
Think of the other people for once, that is what this virus is about.
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