Exit polls showed a record turnout among conservative voters.
Reid beat tea party challenger Sharron Angle in a hotly contested Nevada Senate race that was neck-in-neck in recent polls.
The GOP captured six other Senate seats previously held by Democrats, including the Illinois seat formerly held by President Barack Obama.
Meantime in the House, John Boehner, who is expected to be the new speaker, says he received a congratulatory phone call from Obama. Boehner said he told Obama that Americans expect them to cut spending and create jobs.
Republican Rand Paul coasted to victory in Kentucky, in what was the first major victory of the night for the Tea Party movement.
Paul's victory over Democrat Jack Conway was seen as an early indication of Republicans' return to prominence in Congress and a sign of the Tea Party movement's growing political influence.
All 435 seats in the House were on the ballot, plus 37 in the Senate in an election shadowed by recession and stirred by a rebellion of tea party conservatives.
An additional 37 governors' races gave Republicans ample opportunity for further gains halfway through Obama's term.
Republicans captured Democratic governorships in at least 10 states Tuesday, including some prime presidential battlegrounds.
In Ohio, a state viewed by both parties as crucial to the 2012 presidential election, former Rep. John Kasich defeated Gov. Ted Strickland. Republican Susana Martinez won the New Mexico governorship - she is the first Latina chief executive of a state - and will succeed Democratic Gov. Bill Richardson.
As the polls close across the country, ABC News projects the latest winners for U.S. Senate:
- Alabama: Republican incumbent Richard Shelby
- Arizona: Republican incumbent John McCain
- Arkansas: Republican challenger John Boozman
- California: Democratic incumbent Barbara Boxer
- Connecticut: Democrat Richard Blumenthal
- Delaware: Democrat Christopher Coons
- Florida: Republican Marco Rubio
- Georgia: Republican Johnny Isakson
- Hawaii: Democratic incumbent Daniel Inouye
- Indiana: Republican challenger Dan Coats
- Idaho: Republican incumbent Mike Crapo
- Illinois: Republican Mark Kirk
- Indiana: Republican Dan Coats
- Iowa: Republican Chuck Grassley
- Kansas: Republican Jerry Moran
- Kentucky: Republican incumbent Rand Paul
- Louisiana: Republican incumbent David Vitter
- Maryland: Democratic incumbent Barbara Mikulski
- Missouri: Republican Roy Blunt
- Nevada: Democrat Harry Reid
- New Hampshire: Republican Kelly Ayotte
- New York: Democrat Chuck Schumer and Democrat Kirsten Gillibrand
- North Carolina: Republican incumbent Richard Burr
- North Dakota: Republican John Hoeven
- Ohio: Republican Rob Portman
- Oklahoma: Republican Tom Coburn
- Oregon: Democrat incumbent Ron Wyden
- Pennsylvania: Republican Pat Toomey
- South Carolina: Republican incumbent Jim DeMint
- South Dakota: Republican John Thune
- Utah: Republican Mike Lee
- Vermont: Democratic incumbent Patrick Leahy
- West Virginia: Democrat Joe Manchin
- Wisconsin: Republican Ron Johnson
Projections may not be made for Colorado, Alaska and Washington on Tuesday night. Colorado's race is too tight, while Alaska and Washington ballots could take some time to confirm.
ABC News and The Associated Press contributed to this report.