The opposition Democrats are hoping to retake control of the House of Representatives, while Republicans seek to tighten their grip on the Senate.
Turnout is expected to be high, with more than 34 million Americans already having voted in the election.
Both Donald Trump and Democrat Barack Obama rallied supporters on Sunday.
“You gotta get to the polls on Tuesday, and you gotta vote,” Mr Trump said in Macon, Georgia. “The contrast in this election could not be more clear.”
In recent days Mr Trump has ramped up his rhetoric on issues like immigration, accusing Democrats of wanting to “erase America’s borders” at a rally in Tennessee.
Meanwhile Mr Obama urged Americans not to succumb to hostility and division.
“We have seen repeated attempts to divide us with rhetoric designed to make us angry and make us fearful,” the former president said in Miami.
“But in four days, Florida, you can be a check on that kind of behaviour.”
Mr Trump continues campaigning in Ohio and Indiana on Monday, before making a final stop in Missouri.
Why are voters so energised?
Immigration remains a hot topic that both main parties have sought to capitalise on.
Democrats believe the president’s hard-line rhetoric will help them entice younger voters, suburban moderates and minorities to the polls.
Republicans are counting on Mr Trump’s tough posture to turn out conservatives who think Democrats care more about illegal immigrants than US citizens.
His recent decision to send 5,000 troops to the Mexican border as a caravan of Central American migrants approaches has divided opinion.
The gun control movement launched in the aftermath of February’s high school shooting in Parkland, Florida, has also mobilised.
But one of US voters’ major concerns is healthcare, as Republicans have been trying, so far unsuccessfully, to kill off Mr Obama’s Affordable Care Act.
Some recent events have added a further emotive dimension.
Both events prompted Mr Trump’s critics to blame the president for helping to create an atmosphere in which the attackers felt able to commit their crimes.
What is happening with turnout?
Turnout is traditionally low in the US mid-terms, with the 2014 election seeing a post-war record low of just 37%.
But analysts say a sharp rise is likely this year, with voters on both the left and the right energised by such issues as healthcare and immigration.
The companies are offering paid time-off and other schemes to give employees a better chance to vote.
Ride-sharing companies Lyft and Uber will be offering discounted rides to polling stations.
What is at stake in these elections?
Americans are voting for all 435 seats in the House of Representatives, and 35 of the 100 Senate seats.
Governors are also being chosen in 36 out of 50 states. In Florida and Georgia, Democrat candidates are hoping to become their states’ first African American governors.
Democrats are confident of overturning the Republican majority in the House, but a booming economy is likely to favour the Republican incumbents.
But in the Senate most of the seats being contested are currently held by Democrats. Some are considered vulnerable, as they are in states won by Mr Trump when he was elected in 2016.
So the Republicans could potentially increase their majority in the Senate.
But even losing the House would be a blow for Mr Trump, as the situation would create a potential for legislative gridlock and even government shutdown.
The key races to watch
The first polls close at 23:00 GMT (18:00 EST) on Tuesday and while it will take some time to see the full picture emerge, there are some races worth keeping an eye out for.
Democrats need to make gain 23 seats in order to take the House – take a look at vulnerable House seats which Republicans currently hold in and around Orange County in California, for example.
In the Senate, Democrats have high hopes of gaining Republican-held seats in Arizona and Nevada.
They would need to make a gain of two seats to win control the Senate – but also risk losing their own Senate seats in North Dakota and Missouri.
The races for governor in Florida and Georgia are also too close to call.