The first polls opened at 6 am (1000 GMT) in New Jersey, with voting to begin four hours later in California, the country's most populous state.
Passing the milestone of 2,383 delegates late Monday secured Clinton's status as the presumptive Democratic nominee, and she becomes the first female standard-bearer of a major US political party.
It's a dramatic political resurgence for a highly experienced but controversial candidate who lost to Barack Obama in their 2008 battle for the Democratic nomination.
But Sanders was not ready to capitulate, insisting the Democratic nominee will not be chosen until delegates vote at the party's national convention in late July.
And while her campaign acknowledged the US network tallies that pushed her over the line were "an important milestone," Clinton said the Democratic race was not yet over.
"We are on the brink of a historic, historic, unprecedented moment," she told a rally in Long Beach, California.
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