Ahead of the results, US stocks closed higher, with the benchmark S&P 500 Index ending the day at a two-week high.
House Minority Leader Nancy Pelosi, in line to become speaker, said while there is common ground on infrastructure and cutting the cost of prescription drugs, the investigations will commence.
It also will test Trump's ability to compromise, something he has shown little interest in over the last two years with Republicans controlling both chambers of Congress.
However, initial results - like the flipping by Jennifer Wexton of a previously solidly Republican Virginia seat in the House - signalled that pre-election predictions of Democrats taking over the lower chamber may be confirmed.
Trump was watching the results alongside friends and family at the White House, his spokeswoman said.
She says, "Maybe you get a ripple but I certainly don't think that there's a blue wave".
President Trump called Pelosi Tuesday night to offer congratulations, her office said.
With a House majority, Democrats will have the power to investigate Mr Trump's tax returns, possible business conflicts of interest and allegations involving his 2016 campaign's links to Russian Federation.
Two unexpectedly hard races in deep-red states went to Republicans.
Heitkamp lost to GOP Rep. Kevin Cramer, whom Trump persuaded to seek the Senate seat.
The White House for days has been stressing the historical headwinds it faced: In the last three decades, 2002 was the only midterm election when the party holding the White House gained Senate seats.
The result upends the balance of power in Washington, where Trump has enjoyed an easy ride from Republican dominance of both houses of Congress since his shock election in 2016.
Democrats have had mixed success in districts that backed former President Barack Obama and flipped to backing Trump.
Discussion about the possibility of impeaching the President is also likely to grow louder in a Democratic-controlled House, despite the fact that Democratic congressional leaders have tried to tamp down on speculation that the party might pursue impeachment - at least at this point.
Republicans had expected the GOP tax plan would be the cornerstone of their election agenda this year, but it became a potential liability in key states along the East and West coasts where residents could face higher tax bills because of limits on property and sales tax deductions.
"We need to keep the Senate Republican to support the agenda of Donald Trump", he said.
Health care and immigration were high on voters' minds as they cast ballots, according to a wide-ranging survey of the American electorate conducted by AP.
Nearly a quarter of voters considered immigration to be the top issue, while another one-fifth said it was the economy.
Voters also had mixed views of Trump: About half said they approve of how he is handling his job as president, while just under half said they disapprove of Trump. He said he agreed with Trump on some issues but promised he wouldn't be a rubber stamp.
Trump's scorched-earth campaigning came to define the 2018 campaign.
Down the stretch, Trump hardened his rhetoric on issues that appealed to his conservative core supporters, issuing warnings about a caravan of Latin American migrants headed to the border with Mexico and condemnations of liberal American "mobs".