If Republicans seize a majority, as expected, it would be only the third time in 50 years that control of the House has changed hands, giving a resounding victory to the party that ceded power to Democrats four years ago.
Prospects of a GOP takeover in the Senate appear less likely, although Republicans are expected to make inroads in that chamber, as well.
Exit polling showed anxiety over the economy topped the list of voters' concerns Tuesday and compounded their near-record low approval of their government and the political parties, as seen in recent polls.
Democrats in traditionally blue districts appeared to be neck and neck with their Republican challengers based on early returns in a number of key races.
Iin the Democrat-dominant Virginia suburbs outside Washington, freshman Democrat Gerry Connolly has been under surprising pressure from a conservative businessman he defeated by 12 points in 2008. A Connolly defeat would signal a much broader and deeper wave for the GOP.
Meanwhile, in the district around Cincinnati, which sent Democrat Steve Driehaus to Congress two years ago, the same Ohio voters seem ready to send former seven-term Republican Rep. Steve Chabot back to Washington; a trend seen in a handful of other races across the country.
The strength of a coming Republican wave is also evident in a liberal corner of Hawaii, the state's first district, where 70 percent of voters supported Obama in 2008 but could now send a Republican to represent them in Congress in 2011.
A deep anti-incumbent, anti-establishment mood has also affected veteran Democrats and liberal icons in blue districts, some of who have been in the political fights of their lives, even if they are likely to eek out victories Tuesday.
Missouri Democrat Ike Skelton, who chairs the House Armed Services Committee, John Spratt of South Carolina, who chairs the House Budget Committee, and Jim Oberstar of Minnesota, who heads the House Transportation Committee, have each served more than two decades in Congress but have perhaps never faced a more vigorous reelection challenge.
Even Massachusetts' Barney Frank, one of the most prominent Democrats in the House, and John Dingell of Michigan, the longest-serving U.S. Representative in history, have been threatened by Republican challengers this year.
Mounting the challenges to Democratic incumbents across the country has been a colorful and diverse cast of Republican candidates that includes political rookies, grizzled veterans and Tea Party-backed conservatives.
They include a 28 year-old Republican rocket scientist in Arizona; an Emmy award-winning sportscaster in North Carolina; and a pizza parlor owner in Illinois, all who have kept their Democratic opponents playing defense.
In New York, Republican opthamologist Nan Hayworth is vowing to lead the charge for repeal of Democrats' health care law, while Arizona dentist Paul Gosar is running to oust incumbent Ann Kirkpatrick, who's reelection could hinge on support and turnout among Native Americans.
If the House falls under Republican control and Democrats maintain their hold on the Senate, it would be the first time in 80 years that one chamber has switched hands without the other.