Twelve states cast votes for candidates from either the Republican or Democratic parties or both in a contest seen as make-or-break for the hopefuls.
Contests stretch from Vermont in the east to Texas and Georgia in the south.
After earlier votes in four states, Donald Trump leads the Republican field and Hillary Clinton the Democratic.
The first polls opened in Virginia at 06:00 local time.
Senator Ted Cruz cannot afford to lose to Donald Trump in Texas, his home state, while a reverse for Trump in Massachusetts, with its moderate voters, could break the property tycoon’s nationwide momentum.
Democratic candidate Hillary Clinton is hoping to build on her weekend victory in South Carolina, where she polled heavily among African-Americans, to restore her political fortunes after a bruising defeat in New Hampshire to Bernie Sanders, her self-styled democratic socialist rival.
On November 8, America is due to elect a successor to Barack Obama, a Democratic president standing down after two terms in office which have seen the Republicans take control of both houses of Congress.
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