Despite defeats in the first states to report results, Mr Trump and Mrs Clinton are projected to record wins in the remaining contests.
In the Republican race, Ted Cruz won the Kansas and Maine caucuses.
Bernie Sanders won comfortably in the Democratic Kansas caucuses.
However, billionaire Mr Trump is expected to win in both the Republican Kentucky caucuses and Louisiana primary election.
Former Secretary of State Mrs Clinton is expected to lose to Mr Sanders in the Nebraska caucuses, but partial results from Louisiana put her well ahead.
US elections: Results as they come in
Mr Cruz's wins strengthen his case that he may be the only candidate who can stop Mr Trump after a week in which the Republican establishment did everything it could to attack Mr Trump, analysts say.
The other Republican contenders, Marco Rubio and John Kasich, saw little uplift in their support.
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Donald Trump is currently leading the Republican nomination race
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Bernie Sanders and Hillary Clinton
Observers also also point out that Mr Cruz and Mr Sanders both won in caucuses but appear to have lost in the Louisiana primary elections, involving far more voters. The Democratic race there also appears to have exposed Mr Sanders' lack of support among African-American voters.
The election itself, on 8 November, will see America vote for 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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