He became prebendary of Connor in 1619, and rector of Muckamore in 1622, in which year he was selected by Primate Christopher Hampton to preach at Drogheda on Whit Sunday before the royal commissioners.
He preached before Charles I at Windsor on 9 July 1625, and at Oxford the same year; and on 30 October, being then one of his majesty's chaplains in ordinary, he delivered 'a warning to Israel' in Christ Church, Dublin, dedicated to Lord-deputy Falkland.
In 1628 he was made precentor of St Patrick's Cathedral, Dublin, three other livings being added to the dignity, and in 1632 he became treasurer also, and he seems to have held all these preferments in addition to his deanery.
During the six years which elapsed between the consecration and the beginning of the great rebellion, Leslie was chiefly engaged in conflicts with the presbyterian Ulster Scots, becoming a member of the high commission court in February 1636.
Developments in Scotland gave confidence to presbyterians in Ulster, and on 26 September 1638 Leslie preached at Lisburn against the solemn league and covenant; a Latin version of this sermon, entitled Examen Conjurationis Scoticae, was published by his chaplain, James Portus, in 1639.
This imposed the "black oath", by which every Scot, of either sex and of any age over sixteen, might be made to renounce the covenant and to swear unquestioning obedience to all the king's commands.
A viceregal commission giving him summary power of imprisoning those who refused to appear in his court furnished the ninth article of the impeachment of Strafford (as Wentworth had become).
At the beginning of 1640, Leslie was seriously ill and was unable to attend the parliament which met on 16 March; from his sick bed, he wrote a memorandum for Strafford as to the best means of increasing the royal revenues in Ulster.
The Irish Rebellion of 1641 followed, finding Leslie on 23 October 1641 at Lisburn, writing letters to Lord Montgomery for help, as the news came in of the loss of Charlemont and Newry, and the advance of Sir Phelim O'Neill to Tanderagee.
William's grandson was the father of Theodosia Meade, Countess of Clanwilliam; and through his daughter Rose he was the great-great-grandfather of Stephen Moore, 1st Earl Mount Cashell.