Born in Nancy, he was the eldest son of Antoine, Duke of Lorraine and Renée of Bourbon-Montpensier, daughter of Gilbert, Count of Montpensier. He was briefly engaged in the mid-1530s to Anne of Cleves, who in 1540 would become the fourth wife of King Henry VIII of England.
Francis married the princess of Denmark, Christina of Denmark. The princess was a daughter of King Christian II and Isabella of Burgundy (who had herself been a potential bride of Henry VIII). Francis died at Remiremont in 1545, leaving Christina as the Regent of Lorraine and as the guardian of their young children.
By Christina of Denmark (c.1521 – 1590; married in 1541)