In 1832, Knox was ordaineddeacon and priest by Bishop Beresford of Kilmore. On 7 May 1834 he became chancellor of Ardfert. On 16 October 1841 he was collated as prebendary of St Munchin's, Limerick, by his uncle Edmund Knox, Bishop of Limerick, who also made him his domestic chaplain.[1]
Knox was nominated to the see of Down, Connor, and Dromore by George Villiers, 4th Earl of Clarendon, at the time Lord Lieutenant of Ireland. Samuel Wilberforce later reported in his diary for 26 August 1861, some gossip about this appointment; James Henthorn Todd had said of Knox that he was "…very foolish, without learning, piety, judgment, conduct, sense, appointed by a job, that his uncle should resign Limerick", while Anthony La Touche Kirwan (Dean of Limerick, died 1868), said that Knox "…used, when made to preach by his uncle, to get me to write his sermon, and could not deliver it".[1][3]
Nevertheless, Knox was the author of various ecclesiastical and secular works.[2]
Knox made no secret of his view that disestablishment in Ireland was inevitable. As Bishop of Down, Connor, and Dromore, he hoped to build a new cathedral in Belfast, but abandoned this plan in favour of another, to increase the number of churches of the united diocese. He founded the Belfast Church Extension Society in 1862 and through it achieved forty-eight new or enlarged churches. He organized diocesan conferences and founded a Diocesan Board of Missions. In 1867, in the House of Lords, he proposed a reduction of the hierarchy of the Church of Ireland to just one archbishop and five bishops. In person, he was quiet and restrained, pragmatic and frank, and an able administrator and an effective speaker.[1]
Following the death of Marcus Gervais Beresford, Archbishop of Armagh, on 26 December 1885, Knox was chosen as his successor. As president of the General Synod of the Irish church he was seen as fair and moderate. He died at the archbishop's palace, Armagh, on 23 October 1893, and was buried on 27 October in the old ruined church at Holywood.[1] There is also a memorial to him on the north aisle of St Patrick's Cathedral, Armagh.[4]