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Voters unhappy with Obama, worried about the economy and weary of partisan gridlock in Washington set Republicans on what could be a course to control of both chambers of Congress for the first time since elections in 2006.
Republican Senate candidates picked up Democratic seats in Montana, Colorado, West Virginia, South Dakota and Arkansas - giving them five out of the six gains they need for a majority in the 100-member chamber.
The outcome of the elections suggested Obama would face a tougher final two years in office, complicated by greater Republican power and influence in Washington.
In a key Senate race, Republican challenger Tom Cotton defeated Democratic incumbent Mark Pryor in Arkansas, television networks projected, despite frantic get-out-the-vote efforts by former President Bill Clinton, who hails from Arkansas.
Along with Cotton, Republicans Shelley Moore Capito in West Virginia, Mike Rounds in South Dakota, Cory Gardner in Colorado and Steve Daines in Montana also won.
But Democratic Senator Mary Landrieu of Louisiana forced her tough re-election fight into a runoff against Republican Bill Cassidy in Louisiana in December.
Tuesday's elections were deciding 36 senators, 36 state governors and all 435 members of the House of Representatives.
Election Day polling by Reuters/Ipsos found a dour mood among the electorate with less than one-third of voters believing the country is headed in the right direction.
(Additional reporting by Jeff Mason, Susan Heavey, Tim Ryan and Ian Simpson in Washington; Marti Maguire in Raleigh, North Carolina; David Beasley in Atlanta; Steve Bittenbender in Louisville, Kentucky; Barbara Liston in Orlando, Bill Cotterell in Tallahassee and Zachary Fagenson in Miami Beach; Colleen Jenkins in Winston-Salem, North Carolina; Jonathan Kaminsky in New Orleans; Editing by John Whitesides and Frances Kerry)
