According to tracking website FlightAware, the United States has cancelled 2,604 flights, more than half of the 4,529 cancelled worldwide, shortly after 4:30 pm (2130 GMT).
In addition, 3,447 domestic flights were delayed on Saturday, out of a total of 7,602 worldwide for the day.
The worst affected US airline was Southwest, which had to cancel 13 percent of its flight schedule, according to the site.
In the US, airports in Chicago were particularly hard-hit because of difficult weather, with a snowstorm expected in the area on Saturday afternoon and into the night.
The global air travel industry is still reeling from the highly contagious Omicron variant.
Many pilots, flight attendants and other staff are absent from work after contracting COVID-19, or because they are quarantining after coming in contact with someone who has the infection.
Some 7,500 flights were cancelled by airlines worldwide over the Christmas weekend.