In an appearance on Good Morning America, Dr Fauci urged people to keep gatherings limited to those from within the same household.
"You don't want parties with people that you haven't had much contact with, you just don't know if they're infected,” he said.
He added: "So as difficult as that is, at least this time around, just lay low and cool it."
Defending champions Kansas City Chiefs will play the Tampa Bay Buccaneers in the final game of the NFL season on Sunday.
In another appearance on The Today Show, the top infectious diseases expert warned that the celebration could lead to another spike in infections such as those at Christmas and New Year's.
“Every time we do have something like this, there always is a spike — be it a holiday, Christmas, New Year’s, Thanksgiving,” he said.
“As you mentioned, the Super Bowl is a big deal in the United States. Enjoy the game, watch it on television, but do it with the immediate members of your family, the people in your household.”
The warning comes as the Centres for Disease Control and Prevention (CDC) released their own guidance on how to celebrate the event safely ahead of the game on Sunday.
“Gathering virtually or with the people you live with is the safest way to celebrate the Super Bowl this year,” they said.
The agency warned that those who choose to have gatherings with those outside their household should do it outdoors and should maintain social distancing when doing so.
“As much fun as it is to get together in a big Super Bowl party, now is not the time to do that,” Dr Fauci added.
The National Football League announced it will allow a reduced 22,000 fans to attend Super Bowl LV this week, including 7,500 healthcare workers vaccinated against Covid-19.
NFL commissioner Roger Goodell said the decision had been reached “following discussions with public health officials, including the CDC, the Florida Department of Health, and area hospitals and healthcare systems.”
The country’s wave of coronavirus infections has been on the downturn since a spike at the beginning of January, as the nation begins to ramp up its initially slow rollout of vaccinations.
More than 26.6 million people across the US have been infected with the novel disease, leading to the deaths of over 451,000 people.
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