Since the beginning of his reign he sided against the rule of Emperor Charles V, joined to the Coalition of Protestant rebel princes and made an alliance with the long-time enemy of the Habsburgs, King Henry II of France.

This behavior motivated the invasion of Charles V to the Duchy of Legnica and the formal deposition of Frederick III in 1551.

His eldest son Henry XI was made new Duke, but, still a minor, was cared under the regency of his uncle George II of Brzeg.

The abdication of Charles V in 1556 changed Frederick III's situation; the new Emperor, Ferdinand I, restored him in Legnica after his formal promise of obedience and loyalty to him.

In Legnica on 3 March 1538, Frederick III married Katharina (14 April 1518 – 17 November 1581), daughter of Henry V, Duke of Mecklenburg-Schwerin.