The highly-contagious omicron variant is to blame for the uptick, according to the CDC.
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New cases per day have more than doubled over the past two weeks, eclipsing the old mark of 250,000, set in mid-January, according to data kept by Johns Hopkins University.
The fast-spreading mutant version of the virus has cast a pall over Christmas and New Year's, forcing communities to scale back or call off their festivities just weeks after it seemed as if Americans were about to enjoy an almost normal holiday season. Thousands of flights have been canceled amid staffing shortages blamed on the virus.
Dr. Anthony Fauci, the top U.S. infectious-disease expert, said Wednesday that there is no need to cancel small home gatherings among vaccinated and boosted family and friends.
But, "If your plans are to go to a 40 to 50 person New Year's Eve party with all the bells and whistles and everybody hugging and kissing and wishing each other a happy new year, I would strongly recommend that this year we not do that," he said.
Cases in Texas remain high as well, particularly in Harris County, but both hospitalizations and deaths remain at average levels, only seeing slight bumps in the average. That signals that while the cases are surging, the worst cases are not.
The number of Americans now in the hospital with COVID-19 is running at around 60,000, or about half the figure seen in January, the Centers for Disease Control and Prevention reported.
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While hospitalizations sometimes lag behind cases, the hospital figures may reflect both the protection conferred by the vaccine and the possibility that omicron is not making people as sick as previous versions.
COVID-19 deaths in the U.S. have climbed over the past two weeks from an average of 1,200 per day to around 1,500.
Public health experts will be closely watching the numbers in the coming week for indications of the vaccines' effectiveness in preventing serious illness, keeping people out of the hospital and relieving strain on exhausted health care workers, said Bob Bednarczyk, a professor of global health and epidemiology at Emory University.
CDC data already suggests that the unvaccinated are hospitalized at much higher rates than those who have gotten inoculated, even if the effectiveness of the shots decreases over time, he said.
"If we're able to weather this surge with hopefully minimal disruptions to the overall health care system, that is a place where vaccines are really showing their worth," Bednarczyk said.
The Associated Press contributed to this article.
See related post: Global COVID cases up by 11% last week, omicron risk 'remains very high': WHO