Obama and his left-leaning Democratic Party have been in damage-control mode for months as voters are expected to vent their frustrations at an economy and labour market that have remained sluggish.
"I think the loudest voices will drive the story," said David Goodman, 34, a defence contractor who had just cast his vote in upscale, liberal Rockville, Maryland, outside the nation's capital.
Opinion polls have suggested a landslide could be in the making. Gallup's final poll Monday found that 55 percent of likely voters preferred Republican candidates, while only 40 percent would elect Democrats.
Obama's approval ratings have fallen below 50 percent during his second year in office, as unemployment remains near 10 percent and voters feel the government has overreached with massive spending programmes and reforms of health care and the financial sector.
Steve Krasnow, 59, a lifelong Democrat, reflected the deep disillusionment many Democrats have with their president, saying the country needed to get back to its "entrepreneurial spirit".
"We had a bad president as a Republican (Bush) - this guy (Obama) is even worse," he said as he headed to vote.
All 435 seats in the House of Representatives and 37 seats in the 100-member Senate are up for grabs in Tuesday's election, as well as 37 state governorships and many more state and local elections.
The polling suggests Republicans are highly likely to gain more than the 39 seats they need to reclaim a majority in the lower House. Control of the Senate is less certain, but likely to remain in the hands of Democrats, who have held majorities in both chambers of Congress since 2006.
The conservative movement has been galvanized this election cycle by the rise of the Tea Party, a grassroots movement that arose out of voters who were angry with incumbent politicians and the expansion of government under Obama.
Tea Party-backed candidates toppled a series of more established Republicans in primary races with their outsider message, but have been branded extremists by Democrats and some Republicans.
The Republican Party's takeover of Congress, together with the Tea Party's uncompromising stance on most political issues, has many predicting legislative gridlock during Obama's next two years in office leading up to the 2012 presidential elections.