The government issued a brief statement which said the 41-year old had resigned.
Prime Minister Matteo Renzi was expected to name Mogherini's replacement later in the day.
Negotiations with Italy's President Giorgio Napolitano on Thursday failed to result in an appointment, indicating disagreements over the best candidate.
According to Italian media reports, 39-year old Renzi is keen for a female foreign minister in order to maintain gender equality in his cabinet, but the candidates put forward have not gone down well with the head of state, who has the power to appoint new ministers.
The reports said Napolitano favours current deputy finance minister Lapo Pistelli for the post.