He was the son of Paolo Giordano I Orsini and Isabella de' Medici, and inherited his father's titles and fiefs after his death in 1585.

In 1589 he married Flavia Peretti, a niece of Pope Sixtus V, by whom he had 12 children.

[2] His son Paolo Giordano became a prince of the Holy Roman Empire through his marriage with Isabella Appiani, princess of Piombino.

Virginio Orsini was a supporter of the Earl of Essex and visited the English court for the Christmas revels in December 1600.

By his wife, Flavia Damasceni Peretti, he had twelve children, eight sons and four daughters:[7]