The dead included one suspected gunman, the university president, Charles Steger, told reporters.
The rampage took place in two separate areas, first at a dormitory as students began criss-crossing the sprawling campus for morning classes, and then about two hours later at an engineering and science hall just under a kilometre away.
The attacks sparked panic and chaos.
The 15 wounded included people shot and those hurt jumping from windows to escape the gunfire, Virginia Tech campus police chief Wendell Flinchum said.
Flinchum said the suspected gunman killed himself during the rampage.
"All I can tell you is that he's a male," Flinchum said, giving no details of his age or nationality. He also did not say how well-armed the suspected gunman was.
However, other reports said the gunman was Asian American, and carried two nine-millimetre handguns.
"We have not confirmed the identity of the gunman because he carried no identification on his person and we are in the process of attempting that identification," Steger said.
Students told CNN there were multiple bomb threats to the campus in the last few weeks. Two of the threats were aimed at the university's science and engineering school.
A US Department of Homeland Security spokesman said there was no indication of terrorism but that it would be part of the investigation.
"Today our nation grieves with those who have lost loved ones at Virginia Tech," President George W Bush said.
A student journalist's video of the chaos at Virginia Tech, a state university, was replayed repeatedly on US television networks.
It showed people scurrying around the campus and more than two dozen shots ringing out.
The death toll was worse than a massacre at the University of Texas in Austin on August 1, 1966, when Charles Whitman, a 25-year-old student, killed 13 people and wounded 31 in a 90-minute spree. Whitman had killed his mother and wife the night before.
The first shooting at Virginia Tech was reported to campus police at about 7.15am (11.15pm NZT) in West Ambler Johnston Hall, a dormitory housing some 900 students.
It was followed by more shooting at Norris Hall, site of the science and engineering school that has given the university much of its fame as a leading technical institute in the United States.
During the two hours after the first shooting some students had ventured out again. University police were investigating the first shooting at the dormitory when they got word of gunfire at the classroom building.
Student Justin Merrifield said he was outside West Ambler dormitory at 9am when he saw police and a crying student but did not realise the magnitude of the crisis until he arrived at his 10am class.
Merrifield said students were alerted by campus loudspeakers.
"There was a voice that just kept repeating, 'Gunman on campus, stay indoors, get away from windows,' over and over, basically," said Merrifield.
Steger, facing a barrage of questions over the university's initial response, stressed that its efforts to alert students could not possibly reach the thousands of people moving around the campus at the start of the school day.
"We had no reason to suspect any other incident was going to occur," Steger said of the first shooting.
One student criticised how university officials reacted.
"I'm pretty outraged that someone died in a shooting in a dorm at 7 o'clock in the morning and the first e-mail about it had no mention of locking down the campus, no mention of cancelling classes," Jason Piatt told CNN.
"They just mentioned that they were investigating a shooting," he said. "That's pretty ridiculous. Meanwhile, while they sent out that email, 21 people got killed."
The shooting was bound to revive debate in the United States about gun violence.
"We live in a society where guns are pretty well accepted," said Jim Sollo, of Virginians Against Handgun Violence.
"There are 200 million guns in this society and obviously some in the wrong hands."
Virginia Tech, with 26,000 students and some 100 buildings on 1,050 hectares, is located in the town of Blacksburg and set in lush rolling hills in the southwest corner of the state, about 390km from Washington.
Classes were cancelled for Monday and Tuesday and counsellors were being brought in to talk to the students.
The first shooting at Virginia Tech, a state university, was reported to campus police at about 7:15am (11.15pm NZT) in West Ambler Johnston Hall, a dormitory housing some 900 students.
Virginia Tech closed for a day last August 21 because of a manhunt for an escaped prisoner. William Morva, accused of shooting and killing a hospital guard and then a sheriff's deputy near the Virginia Tech campus while on the run, was captured a day after escaping custody on August 20.