Son of William Fitzalan (1483–1544), the 11th earl, he succeeded to the earldom in 1544. He took part in the siege of Boulogne (1544) and was appointed lord chamberlain and a privy councillor in 1546. In June 1553 he alone of the council refused the “engagement” of the council to support Edward VI's “device” for the succession—which passed over his sisters, Mary and Elizabeth, as illegitimate, in favour of Lady Jane Grey. He did, however, sign the letters patent. On Edward's death, while pretending to support Northumberland, he secured the proclamation of Mary as soon as Northumberland had left London.

Under Mary I he held a series of high appointments, including the lord stewardship, which he retained under Elizabeth I. But as one of the leaders of the Catholic nobility he fell under suspicion, resigned his offices in 1564, and was more than once disgraced. In 1569 he was implicated in the intrigues of Thomas Howard, 4th duke of Norfolk, but, although he appears to have received money from Spain, the evidence against him was insufficient, and he was released in March 1570 and even recalled to the council. After the discovery of the Ridolfi plot he was once more arrested and liberated only after the execution of Norfolk in 1572. At his death the title passed through his daughter Mary, the wife of the beheaded Norfolk, to the Howards.