The closures include Interstate 70 in both directions between Burlington and Limon and I25 in both directions from Wellington to the state line.
Other roads affected include several U.S. and state highways.
Air travel is being snarled, too. More than 2,000 flights were canceled this weekend at Denver International Airport.
The FAA urged travelers to check their flight status before heading to the airport.
More than 1,300 flights were canceled into or out of Denver Sunday, after more than 700 were called off on Saturday. MOre than 125 have been canceled for Monday. United Airlines suspended all weekend flights out of Cheyenne Regional Airport in Wyoming.
United, Southwest and Frontier, among other airlines, waived fees for people who need to change tickets originally booked for this weekend.
Dangerous driving conditions, power outages and an increased avalanche risk were among the hazards as Colorado, Nebraska and Wyoming braced for the winter storm that forecasters said could be of historic proportions.
About 13,000 homes and businesses were without power Sunday morning in Colorado, according to poweroutage.us.
Gov. Jared Polis had activated the state's National Guard to be ready for search and rescue efforts if needed.
"I urge you to stay home if it's going to snow hard in your area so you don't need them to rescue you," Polis said.
The storm was forecast to dump several inches of snow in some areas.
The Colorado Avalanche Information Center issued an avalanche warning Sunday morning for the Front Range area and advised against backcountry travel. A watch had previously been in effect.
"Intense snowfall will cause large and destructive avalanches," the warning said. "Expect avalanches in unusual locations with strong easterly winds and deep snow at all elevations. Avalanches will be easy for backcountry travelers to trigger and can run naturally during periods of high snowfall rates. Backcountry travel is very dangerous and not recommended."
Shoppers in Denver stripped grocery store shelves bare ahead of the storm as they readied themselves to be stuck at home for several days. Power outages were possible.
First responders said they were prepared for the storm and expected to handle calls related to falls, shoveling snow and car crashes, the Denver Post reported.
"We are constantly at the ready to be able to help people," Denver Fire Department spokesperson Greg Pixley said. "If the snow is going to be an issue, we will address it."
Mark Becker, a Nebraska Public Power District spokesman, said wet snow could weigh down tree branches and bring down power lines.
"Our crews will respond as quickly as possible, but safety is a priority for them as well," Becker told the Star Herald.
He reminded people to not use generators indoors or near enclosed spaces. Grills or other makeshift heating devices also should not be used inside. Hundreds of cases of carbon monoxide poisoning and several deaths were reported during and after extreme winter weather that hit Texas last month.
Travel by road is expected to become difficult if not impossible in some areas.
The Colorado High School Athletic Association postponed playoff games scheduled for Saturday.
Motorists planning weekend travel are urged to get where they need to be before this evening. Several major interstates could be affected.
Heavy accumulations are possible along Interstate 70, I-25 and other highways in the foothills and the Front Range, the Colorado Department of Transportation warned.
The department said it is likely to close these roadways for safety reasons depending on the severity of the storm.
Snowplow crews will focus on clearing I-25, I-70 and other interstates. Secondary routes will not be plowed until the worst of the storm has passed, the department said.
The city of Denver planned to deploy plows as needed throughout the storm.
"With significant snowfall amounts anticipated, we request that you please don't drive if you don't have to drive and give the plows plenty of space to operate," a city news release said.
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