Anthony St Leger was the eldest son of Ralph II St Leger of Ulcombe in Kent, by his wife Isabel (or Elizabeth) Haute. She was the daughter of Richard Haute (d. 8 April 1487) by his wife Elizabeth Tyrrell, widow of Sir Robert Darcy (c.1420 - 2 November 1469) of Maldon, Essex, and daughter of Sir Thomas Tyrrell (d. 28 March 1477) of Heron in the parish of East Horndon, Essex.
He was educated abroad and at the University of Cambridge. He quickly gained the favour of King Henry VIII (1509–1547), and in 1537 was appointed president of a commission of enquiry into the condition of Ireland. In the course of this work, he obtained much useful knowledge of the country. In 1539, he was knighted and appointed Sheriff of Kent.
On 7 July 1540, Sir Anthony was appointed Lord Deputy of Ireland and tasked with the repression of disorder. He moved against the MacMorrough Kavanagh clan, who had long claimed the title of King of Leinster, permitting them to retain their lands only by accepting feudal tenure on the English model. By a similar policy, he exacted obedience from the O'Mores, O'Tooles and O'Conors in Leix and Offaly. Having conciliated the O'Briens in the west and the Earl of Desmond in the south, he obtained the passage of an act in the Irish Parliament in Dublin, which conferred the title of King of Ireland on King Henry VIII and his heirs. Conn O'Neill, who had remained sullenly hostile, was forced to submit.
St Leger's policy was generally one of moderation and conciliation, more so than Henry VIII wished. He recommended the head of the House of O'Brien, when he gave token of a submissive disposition, for the title of Earl of Thomond. O'Neill was created Earl of Tyrone. At St Leger's urging, the King in 1541 created six new Irish peerages. St Leger argued that the loyalty of the Anglo-Irish nobility could be better achieved "by small gifts and honest persuasion than by rigor", which seems to be an implicit criticism of the savage manner in which the Rebellion of Silken Thomas had been suppressed. St Leger's policy of conciliation seems to have been successful: in particular, the Plunkett family, who received the title of Baron Louth, became steadfast loyalists to the English Crown, as did the Fitzpatrick family, who received the title of Baron Upper Ossory. Barnaby Fitzpatrick, 2nd Baron Upper Ossory grew up at Henry VIII's court, and he was a beloved childhood friend of Henry's son, Edward VI.
An administrative council was instituted in the province of Munster, and in 1544, a levy of Irish soldiers was raised for service in Henry VIII's wars. St Leger's personal influence was proved by an outbreak of disturbance when he visited England in 1544, and the prompt restoration of order upon his return some months later. St Leger retained his office under King Edward VI (1547–1553), and again effectively quelled attempts at rebellion by the O'Conors and O'Byrnes. From 1548 to 1550, Sir Anthony was in England and returned to Ireland charged with the duty of introducing the reformed liturgy into that island. His conciliatory methods led to his recall in the summer of 1551. After the accession of Queen Mary (1553–1558), he was again appointed Lord Deputy in October 1553, but a charge of keeping false accounts caused him to be recalled for the third time in 1556. He died while the accusation was still under investigation, by which time, in 1559, he had been elected Member of Parliament for Kent.