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She married her maternal uncle King Ferdinand VII of Spain in 1816, whose first wife, Princess Maria Antonia of Naples and Sicily, had died ten years before.

The marriage produced one daughter, the Infanta María Luisa Isabel, who was born on 21 August 1817; she died on 9 January 1818 in Madrid; Maria Isabel was again pregnant soon after the birth of her firstborn, but the birth was a difficult one. The baby was in breech and the physicians soon found that the child had died. Maria Isabel stopped breathing soon thereafter and the doctors thought she was dead; when they started cutting her up to extract the dead fetus, she suddenly shouted in pain and collapsed on her bed, bleeding heavily. She died on 26 December 1818 in the Royal Palace of Aranjuez and was buried at the Escorial, having failed to provide her husband with an heir to the throne.

It is due to Queen Isabel's dedication and affection for the art world that she managed to gather many treasures from the past and create a royal museum, which would end up being the beginnings of Museo del Prado. It opened on 19 November 1819, a year after the Queen's death.