Voting has begun on the East Coast at 06:00 EST , though some villages in New Hampshire have already polled.
Both candidates criss-crossed America in a hectic last-minute campaign push for votes.
Results should begin emerging late on Tuesday night.
Hillary Clinton urged voters to back a “hopeful, inclusive, big-hearted America” while Donald Trump told supporters they had a “magnificent chance to beat the corrupt system”.
Polls give Hillary Clinton a four-point lead over Donald Trump.
A record number of Americans – more than 46 million – have voted early by post or at polling stations.
There are signs of a high turnout among Hispanic voters, which is believed to favor Hillary Clinton.
The candidates held the final rallies of their campaigns after midnight – Donald Trump in Grand Rapids, Michigan, and Hillary Clinton in Raleigh, North Carolina.
Election Day follows a bitter campaign during which the candidates have traded insults and become mired in a series of scandals.
At a star-studded event in Philadelphia, Pennsylvania, Hillary Clinton was joined on stage by celebrities Bruce Springsteen and Jon Bon Jovi as well as her husband Bill, President Barack Obama and the First Lady.
At his rally in Scranton in the same state, Donald Trump insisted the momentum was with his campaign.
He described Hillary Clinton as the “most corrupt person ever to seek the presidency”, referring to an FBI investigation into Clinton’s use of a private email server while she was serving as secretary of state between 2009 and 2013.
Election Day voting began just after midnight in the small New Hampshire village of Dixville Notch, where seven votes were cast – four for Hillary Clinton, two for Donald Trump and one for the libertarian Gary Johnson.
Results are expected sometime after 23:00 EST once voting ends on the West Coast. State projections will not be available until polling ends – in most states between 19:00 EST and 20:00 EST.
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