He said the longer Christmas/New Year period may be even more of a challenge.
The US is seeing peak infections of close to 200,000 a day on average with record numbers of people in hospital.
California is under a strict new lockdown, with other states announcing record increases.
The US has recorded more than 14.7 million cases of infection in the pandemic so far and 282,500 deaths, according to Johns Hopkins University research, both global highs.
President Donald Trump has been accused of playing down measures such as mask wearing but the US has also had to deal with different states taking different approaches to tackling the virus.
Dr Fauci, who has been asked by President-elect Joe Biden to be his Covid chief medical adviser, told CNN his concerns for Christmas were the same as his concerns for Thanksgiving, “only this may be even more compounded because it’s a longer holiday”.
He said nobody wanted to modify or shut down the holiday season, but “we’re at a very critical time… we’ve got to not walk away from the facts and the data. This is tough going for all of us”.
Millions defied appeals from experts not to travel over the Thanksgiving period – the Sunday after the Thursday 26 November holiday saw the most air travellers since March and the Covid effects are still to be fully felt.
Dr Fauci, who has been part of the Trump administration’s response to Covid-19 but has also drawn criticism from the president for his views, said people tended to return to work the week following Thanksgiving but that this is often not the case with Christmas leading into New Year.
On Sunday, former Food and Drug Administration (FDA) commissioner Scott Gottlieb said US deaths could be near 400,000 by the end of January, adding: “As bad as things are right now, they’re going to get a lot worse.”
Also on Sunday, Dr Deborah Birx, the White House coronavirus task force co-ordinator, criticised the Trump administration for flouting guidelines and peddling “myths” about the pandemic.
California has ordered much of the state to stay at home, after it set a daily record of 30,000 new cases on Sunday.
In the south of the state, fewer than 15% of intensive care hospital beds are empty.
Dr Fauci told Californian officials they “really don’t have any choice” in imposing some of the strictest measures in the US, including bans on restaurant dining and private gatherings.
The lockdown, affecting around 85% of the state’s 40 million people, will last for at least three weeks and until Intensive Care Unit (ICU) capacity goes above 15% again.
New York’s Governor Andrew Cuomo has called on retired doctors and nurses to return to work and said if the number of patients in hospital did not decrease in five days, indoor dining in New York City would stop.
But New York did reopen some of its schools on Monday, allowing some in-person instruction at younger ages – a move guided by figures showing lower Covid positivity rates in schools.
Massachusetts Governor Charlie Baker said the state had witnessed a post-Thanksgiving surge, saying infections “took off like a rocket”.
New Jersey, North Carolina, Virginia and West Virginia have also announced record one-day rises in new cases.
The FDA could authorise the Pfizer vaccine – approved in the UK – on Thursday, with vaccinations taking place just a few days later.
They will be rationed and targeted but the Trump administration hopes to vaccinate as many as 24 million people by mid-January.
Source: News Agencies and BBC