Students from more than 2,600 schools and institutions planned to leave their classes at 10:00 a.m. local time, organizers said.
It was the second student walkout since the Feb. 14 massacre of 17 people at Marjory Stoneman Douglas High School in Parkland, Florida, and the emergence of a national student movement to end gun violence and tighten gun restrictions.
Many of the demonstrators wore orange, a colour that has come to represent the movement against gun violence, as they observed a 13-second silence in honour of those killed at Columbine.
"I'm trying to get an education, but I still have a small fear that someone will come in with a gun," said Ayanna Rhodes, 14, who walked out of Washington International School to join hundreds of local students in front of the U.S. Capitol. "It's an issue that's been in this country for a long time."
Two gunman went on a shooting rampage at the Colorado high school in 1999, leaving 12 students and a teacher dead before killing themselves. The massacre stunned the nation but since then, school shootings have become commonplace.
Even as students prepared for their protest on Friday morning, news began trickling out that one person was wounded in a shooting at a high school near Ocala, Florida.
The latest gun violence unfolded about 225 miles (360 km)northwest of the Parkland high school, where two months ago a former student killed 17 people in the deadliest high school shooting in U.S. history.
Dudley Brown, president of the Colorado-based National Association for Gun Rights, said the gun-control movement seeks to have the government take away constitutional rights.
"The main objective of these students is to ban firearms completely, and confiscate the firearms of law-abiding Americans," Brown said. "We will oppose them at every step."
Students walked out of high schools in New York, Detroit and Washington, among hundreds of other cities and towns. Many were waving placards with slogans such as "No more gun violence" and "I should be worried about grades, not guns."
Outside the White House, scores of young protesters sat in silence while they listened to the names of gun violence victims read aloud.
After walking out of class and observing the 13-second silence, students were free to decide how to demonstrate. National organizers suggested marches to the offices of local lawmakers, speeches, and voter registration activities.
On the evening before the national walkout, Colorado gun control activists rallied near Columbine High School, calling for an end to gun violence.
Carlos Rodriguez, a 17-year-old junior from Marjory Stoneman, traveled to Columbine for the anniversary, and said he found a sense of solidarity in the outpouring of support.
"That's the only thing that's keeping us Douglas students alive right now: the distraction of fighting for our rights and advocating for our lives," Rodriguez told Reuters. "It's the one thing keeping us hopeful, it's the one thing keeping us from not being able to sleep at night."
Columbine has not held classes on April 20 since the massacre, a district spokeswoman said, so there would be no walkout at the school. Students were encouraged to take part in community service.
The latest national rally came more than a month after tens of thousands of students from some 3,000 schools participated in the #ENOUGH National School Walkout to demand that lawmakers seek tighter gun control regulations.
It also followed "March For Our Lives" rallies in cities across the United States on March 24 that were some of the biggest U.S. youth demonstrations in decades, with hundreds of thousands of young Americans and their supporters taking to the streets to demand tighter gun laws.
It was not immediately clear whether Friday's turnout would match those of the earlier protests.
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