She said many young African-Americans have disenfranchised themselves because only about 20 per cent of them voted in the 2014 midterm elections.
"You can hashtag all over Instagram and Twitter, but those social medial movements will disappear faster than a Snapchat if you're not also registered to vote," Obama told an estimated 35,000 people, including 800 graduates of Jackson State University.
She said if people fail to exercise the fundamental right to vote, rights will be under threat.
"We see it right here in Mississippi, just two weeks ago, how swiftly progress can hurdle backward, how easy it is to single out a small group and marginalize them because of who they are or who they love."
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She noted that Mississippi Veterans Memorial Stadium, where she spoke under clear blue skies, was built in the 1950s and was only used by white football teams until 1967, when Jackson State and Grambling State became the first black teams to play there.
She also noted that in 1962, the stadium was the site of "what was essentially a pro-Jim Crow rally" with University of Mississippi fans waving Confederate flags and singing a song called, "Never, No Never" to protest the admission of the university's first black student.
Obama has spoken at a historically black college or university each year since her husband became president, the White House said. Her appearance at Jackson State is one of three commencement addresses she will make this year.
The others are May 26 at the Santa Fe Indian School and June 3 at the City College of New York campus in Harlem.
She and President Barack Obama socialized with members of the British royal family Friday in London.