The Republican is one of the country's most prominent Cuban-American politicians and has been a strong opponent of Cuba's communist government.
Shortly after Thursday's announcement, his brother Mario, a congressman representing the district neighboring his brother's, said he plans switch districts and run for the vacated seat.
Lincoln Diaz-Balart says he plans to return to his law practice.
He won a special election for Florida's 21st district in 1989 and went virtually unchallenged until last year when fellow Cuban-American and former Hialeah mayor Raul Martinez ran against him.
His family fled Cuba for Miami when he was a child, but his brother was born in Florida.