In the Senate, Majority Leader Harry Reid won a tough re-election battle against Republican challenger Sharron Angle.
"Today, Nevadans chose hope over fear. Today Nevadans chose to move forward, not backwards," Reid told supporters. "You made possible what many thought was impossible."
Democrats also were poised to capture a key win in California, with Barbara Boxer fending off a challenge from former Hewlett-Packard chief Carly Fiorina, projections indicated.
Republicans needed a net gain of 10 Senate seats to wrest control from the Democrats.
But in the midst of Democrats' big wins, there were some big losses as well, projections indicated.
U.S. Rep. Mike Kirk, R-Ill., was projected to take over President Barack Obama's former U.S. Senate seat, media outlets indicated.
Eighteen-year veteran Sen. Russ Feingold, known for his independent streak, was upended by Republican neophyte Ron Johnson in Wisconsin, results indicated.
Sen. Blanche Lincoln, D-Ark., who ran into opposition from liberals in the Democratic primary, lost to Republican John Boozman.
Tea Party-backed Republican candidate Rand Paul won the U.S. Senate race in Kentucky, defeating Democrat Jack Conway for the seat vacated by retiring Jim Bunning.
"I have a message from the people of Kentucky ... a message that is loud and clear and does not mince words," Paul said in his victory speech. "We've come to take our government back."
The "Tea Party tidal wave," Paul said, was sending a message of "fiscal sanity," limited constitutional government and balanced budgets.
Marco Rubio was the winner in the three-candidate race for Florida's U.S. Senate seat over Democrat Kendrick Meek and independent Charlie Crist, the outgoing governor.
Rubio said GOP wins across the country don't mean voters approve of the Republican Party.
"It would be a grave mistake to view this as an embracing of the Republican Party," Rubio said. "It's a second chance ... to be what they said they would be so long ago."
In Delaware, Democrat Chris Coons defeated Christine O'Donnell, the Tea Party-supported Republican candidate in the race for the seat once held by Vice President Joe Biden.
Even though she lost the general election, her upset win over the GOP establishment candidate means "the Delaware political system will never be the same. ... The Republican party will never be the same," O'Donnell said.
The seat held by the late Sen. Robert Byrd, D-W.Va., will remain in Democratic hands, as popular Gov. Joe Manchin defeated GOP businessman John Raese.
"I'm proud of what we've been able to do" in West Virginia, Manchin told supporters. "When I look at the challenges we have ahead of us in Washington, I have to take the fight there."
Many Senate incumbents on both sides of the aisle, often facing token opposition, were projected the winners in their races by various media outlets.
In a nod to the influence of the Tea Party movement in this year's elections, South Carolina Sen. Jim DeMint, chairman of the conservative caucus, told CNN the results indicated "an awakening going on in our country."
While not committing to founding a Senate Tea Party caucus similar to one in the House of Representatives, DeMint said, "if there is one, I'll join it."
Instead, he said, he'd seek to "expand the conservative caucus to reflect Tea Party ideas."