The lopsided 97-3 vote belied the years of partisan fighting the issue had generated.
Long a Republican priority, the bill drew turnabout support from Democrats and the Clinton administration after disclosures of North Korean missile tests and Chinese weapons espionage.
Republicans welcomed the day-old Democratic backing and the dropping of a long-standing veto threat by President Clinton, although they ridiculed the timing.
"I'm glad to hear he's now dropped his veto threat. But as usual, his pledge comes a little late and falls short," said Sen. Bob Smith, R-N.H., a GOP presidential aspirant.
Four sites in interior Alaska are being considered as bases for the missile system. And Alaska Sen. Ted Stevens said his constituents have told him they want the missile defense system built.
"It was going to pass anyway, probably with enough margin to be the first veto to be overridden," Stevens said. "They knew what they were doing at the White House when they backed up on this one."
Democrats said several amendments, including one pledging that the United States would continue to seek nuclear arms reductions in Russia, made the legislation more palatable.
"The bill is now acceptable to the president," said Sen. Carl Levin, D-Mich., who was the chief Democratic opponent in the past. The earlier version could have violated terms of the 1972 Anti-Ballistic Missile treaty, Levin said.
Ending the impasse helped Democrats defuse an emerging GOP political campaign against them on national security grounds, a campaign that intensified in recent days with reports that China may have stolen nuclear technology from the Los Alamos nuclear laboratory in the 1980s.
Republicans are accusing administration officials of being lax in handling that case when it came to their attention earlier this decade, and also of helping China's missile program more recently through satellite technology exports.
After a closed-door Democratic luncheon on Tuesday, Democratic leaders told the White House they did not know if they could sustain a veto this year, given the popularity of the missile-defense program, Democratic aides said.
Regardless of the current politics, the bipartisan support for the legislation - which is expected to be repeated on Thursday when the House takes up its version of the bill - ends years of divisive debate between the parties.
A missile defense shield has been a top GOP agenda item since President Reagan proposed an ambitious space-based defense system in 1983, dubbed "Star Wars" by critics.
The system now being envisioned is much more moderate, designed to stop a single missile or just a few, probably fired at the United States accidentally or by a roue nation.
Even so, the program is not expected to be inexpensive.
More than $50 billion has already been spent on research and limited testing. Clinton earmarked another $10.5 billion in his budget for it over the next five years, although he had not wanted to make a decision until June 2000 on whether to field such a system.
The Pentagon suggests the earliest a system could be ready is 2005, with or without the legislation.