Entering the service of Henry VIII at an early age, Wriothesley soon made himself very useful to his royal master, and he was richly rewarded when the monasteries were dissolved, obtaining extensive lands between Southampton and Winchester.
Having been on errands abroad, he was made one of the king's principal secretaries in 1540, and was knighted in the same year; in spite of the fall of his patron, Thomas Cromwell, he rose higher and higher in the royal favor, and in 1542 it was said that he governed almost everything in England. He sought to bring about an alliance between England and Spain in 1543, and was created Baron Wriothesley of Titchfield in 1544.
Having been Lord Privy Seal for a few months, he became Lord Chancellor in 1544, in which capacity he became notorious for his persecution of Anne Askew. He was one of the executors of Henry's will, and in accordance with the dead king's wishes he was created Earl of Southampton in February 1547. However, he had committed an offence in appointing four persons to relieve him of his duties as lord chancellor and advantage was taken of this to deprive him of his office in March, when he also ceased to be a member of the privy council.
Again in the council Southampton took a leading part in bringing about the fall of Edward Seymour, 1st Duke of Somerset, but he had not regained his former position when he died. His successor was his son, Henry.