At least four tractor trailers went off the road and a gasoline tanker was engulfed in flames following the crash, which was reported about 11 a.m. MDT. I-25 northbound was closed in both directions but has been reopened, The Denver Post said.
No fatalities were reported in the massive crash but several motorists were taken to area hospitals with various injuries, the Colorado State Patrol said in a release.
Forecasters cautioned people to avoid travel as heavy snow and high winds hindered visibility and made roads treacherous. Interstate 70 was also closed early Saturday, though it had reopened as of midday.
"Travel is going to be tough, with icy and snow-packed roads," said Kyle Fredin, meteorologist for the National Weather Service in Boulder, Colo.
Roads were not expected to clear until Sunday, when winds are forecast to die down in the area.
More than 200 flights were canceled at Denver International Airport as of midday Saturday and many others were delayed by 4 hours.
Parts of Colorado have received a foot of snow during the storm. Boulder received more than 9 inches.
Colorado Department of Transportation spokeswoman Mindy Crane said "the worst of the storm" is headed for the eastern Plains, which was already getting wind gusts of about 40 mph and receiving an inch of snow per hour.