With wins in North Carolina and Iowa, the Republican party picked up at least seven Senate seats to guarantee at least 52 members of the 100-member chamber, TV networks said.
The opposition party needed a net gain of six seats in the Senate.
The Republicans also were on track to extend their majority House of Representatives, networks projected.
Sealing the outcome, television projections showed North Carolina Republican challenger Thom Tillis had outpolled Democratic incumbent Kay Hagan, while Iowa Republican Jodi Ernst beat Democrat Bruce Braley.
In Colorado, Republican challenger Cory Gardner upset incumbent Democrat Senator Mark Udall, based on projections.
Earlier TV network projections showed Republican candidates defeated Democrats in Montana, Arkansas, South Dakota and West Virginia.
By controlling both chambers for the first time since 2006, the outcome complicates the last two years of Obama’s presidency.
CBS News projected the Republicans would hold 245 of the 435 House seats. NBC said the party would take 242 seats.
In the Senate contests decided earlier, Republicans picked up West Virginia when Shelley Moore Capito won the race for the seat vacated by retiring Democrat Jay Rockefeller.
In battleground state Arkansas, Republican challenger Tom Cotton defeated incumbent Democratic Senator Mark Pryor in the home state of former president Bill Clinton.
And in South Dakota, Republican Mike Rounds defeated Democrat Rick Weiland to take the seat of retiring Democratic Senator Tim Johnson, projections said.
Montana also flipped to the Republicans, as Steve Daines topped Democrat Amanda Curtis in a seat that had been Democratic.
In Kentucky, Republican Senate minority leader Mitch McConnell was re-elected, according to projections – putting him in line to be the next majority leader if his party gains control of the upper chamber.
In Georgia, Republican David Perdue was projected to get more than 50 percent, avoiding a runoff in three-way race against Democrat Michelle Nunn and Libertarian Amanda Swafford, CNN and CBS reported. The win keeps the Georgia seat in Republican hands.
Republicans also held Kansas, with incumbent Pat Roberts fending off independent challenger Greg Orman, Fox and CBS said.
A runoff was projected in Louisiana, with incumbent Democrat Mary Landrieu and Republican Bill Cassidy leading a field of nine candidates.
In one consolation for the Democrats, Senator Jeanne Shaheen was re-elected in New Hampshire, fending off a challenge from Scott Brown, a former Republican senator in Massachusetts.
The race in Virginia was far tighter than expected, with Senator Mark Warner, a Democrat, and Republican challenger Ed Gillespie running neck-and-neck, networks said.