Denver police spokesman Sonny Jackson said a man and woman in their 20s were both shot in the leg, The Denver Post reported. They were expected to survive, said the newspaper, which initially reported three people had been shot.
Police said they were looking for two suspects and were asking witnesses from the big crowd that scattered when the shots were fired about 5 p.m. to come forward.
"Everybody fled. That's the problem," Jackson said.
The reason for the shooting had not been determined.
Johnny Lee, who was at the civic center when the shooting erupted, said he didn't hear any disturbance beforehand.
"Everybody started to run," Lee said. "They were running over people."
Damontay Wimberly told the Post he heard about seven shots.
"Pow-pow-pow-pow-pow, about seven times," he said.
Laura Forduno said the event was peaceful right up until the gunfire.
"Everybody was having fun and then you heard the shots -- pow-pow-pow-pow -- and everybody started to run," Forduno said.
"It was chaos."
Several thousand people had gathered in Denver to celebrate marijuana and Colorado's decision to legalize recreational pot consumption.
Organizers said it was the largest gathering in the United States this year for "420 Day," which has become an international rallying time for marijuana advocates, the Post said.
While public pot smoking remains illegal in Colorado, police said law enforcement would be light.
"We're not going to be tackling 10,000 people and writing them all a citation," police spokesman Matt Murray said.
The celebration began at midnight when Snoop Lion, the 41-year-old rap musician born Calvin Cordozar Broadus Jr. who until last year used the stage name Snoop Dogg, threw marijuana cigarettes into the audience at the Fillmore Auditorium.
The High Times Cannabis Cup, a convention usually held in Amsterdam, was transferred to Denver this year. Thousands of people waited outside the EXDO Event Center to get in.
In Boulder, the University of Colorado closed its campus for the second year in a row to prevent a 420 rally. Officials said they would not go as far as they did last year when the quad was sprayed with foul-smelling fertilizer to discourage partying.
Washington state also legalized recreational marijuana use this year. A growing number of states allow medical marijuana.
April 20 is supposed to have become an international day for marijuana because of a group of California high school students 40 years ago. The Post said they used 4-20 as a code for the time they would gather after the end of the school day to share a joint.