The party won in Arkansas, Colorado, Iowa, Montana, North Carolina, South Dakota and West Virginia.
It is expected to post more gains as votes are counted in other states.
Republican Senator Mitch McConnell, poised to lead the chamber, said the result was a vote against “a government that people can no longer trust”.
In the midterms, so-called because they fell half way into Barack Obama’s second four-year term in office, about one-third of the Senate, the entire House of Representatives, 36 of 50 state governors, and countless state and local offices were up for election.
Throughout the campaign, Republicans focused on voter dissatisfaction with Barack Obama, a Democrat, describing the vote as a referendum on his presidency.
As the first results came in late on November 4, it became clear they had made convincing gains in the chamber.
With the votes still being counted in many states, the Republican Party easily won the six seats it needed to win control of the Senate.
The party controls 52 seats, and is tipped to win more.
When the new Congress is sworn in January, it will mark the first time the Republicans have held both chambers since 2006.
They will now have the power to complicate, if not block completely, Barack Obama’s agenda in the last two years of his tenure in the White House.
Control of the Senate will also enable the Republicans to stymie his ability to name new federal judges, cabinet members and senior government officials.
In addition to seats the party won from the Democrats, the Republicans retained seats in Alabama, Georgia, Idaho, Kansas, Kentucky, Maine, Mississippi, Nebraska, Oklahoma, South Carolina, Tennessee, and Texas.
In Louisiana, neither of the top two candidates gained 50% of the vote, forcing a run-off election in early December.
In Virginia, Democrat Mark Warner was expected to retain his Senate seat amid a much tighter than expected race with Republican ex-lobbyist Ed Gillespie.
One of the night’s key early results came in Kentucky, where Mitch McConnell, the Republican Senate minority leader, fended off Democrat Alison Lundergan Grimes.
Mitch McConnell will now become the Senate majority leader, giving him control over the chamber’s legislative agenda and floor proceedings.
“It wasn’t about me or my opponent,” he told supporters as he declared victory, “it was about a government that people can no longer trust.”
Current Senate Majority Leader Harry Reid congratulated Mitch McConnell in a short statement.
“The message from voters is clear: they want us to work together,” said Harry Reid of Nevada, whose role in the soon-to-be Democratic minority remains uncertain.
“I look forward to working with Senator McConnell to get things done for the middle class.”
As well as taking the Senate, the Republicans are projected to increase their majority in the House of Representatives, where all 435 members were up for re-election.
They also made gains among the 36 governorships up for re-election.
Republican governors survived tough re-election battles in Florida, Maine and Wisconsin.
In two results that illustrate the breadth of the Republican sweep, the party’s candidates won in Maryland and Massachusetts, two of the most Democratic-friendly states in the nation. Republican Bruce Rauner also won in Illinois – Barack Obama’s home state – against incumbent Democratic Governor Pat Quinn.
Political gridlock in Congress has already reached historic levels and was a major concern among voters, with many expressing their frustration with the lack of progress on the key issues facing the nation.
Analysts say the Republicans’ victory could make the situation even worse before the president poll in 2016.
Republican leaders have already pledged to move forward on their key policy priorities, pressing Barack Obama to negotiate on their terms
“It’s time for government to start getting results and implementing solutions to the challenges facing our country, starting with our still-struggling economy,” said Republican House Speaker John Boehner.
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