Knox was born in Melbourne and his family later moved to Horsham and Ballarat. He was educated at Scotch College, Melbourne^[2] and joined the State Bank of Victoria in 1866 and worked in various country branches. In January 1884 he married Catherine Mary McMurtrie. In 1885, he became secretary of BHP^[2] and in 1888, his yearly salary was increased from £75 to £1,500. He effectively ran the complex organisation of a company that became Australia's biggest company and the world's biggest silver miner. He resigned as secretary in 1893 to become managing director of the Mount Lyell Mining & Railway Company, but was immediately appointed to BHP's board, a position he retained until 1910.

Knox was a councillor on Malvern Shire from 1892 to 1910 and its president from 1892 to 1895. He was elected to the Victorian Legislative Council to represent South Eastern Province in 1898.^[1] He supported the federation of Australia and was elected as the first member for Kooyong at the inaugural 1901 election, initially as a member of the Free Trade Party, although he later supported some of the protectionist policies of the Protectionist Party. Knox was responsible for moving a motion to begin each sitting day with prayers. He resigned from parliament shortly after his re-election in 1910, having suffered a stroke.^[3] Knox was also one of the seven members of the Prahran & Malvern Tramways Trust, established in 1908 to build part of Melbourne's electric tram network.^[4]

The Knoxs had five sons and two daughters. When he and his wife and their younger children were visiting England in 1913, he died at Folkestone, Kent. He had declined a knighthood. His sons included:

• George Hodges (1885–1960), appointed CMG in 1917, speaker of the Victorian Legislative Assembly (1942–1947)
• Robert Wilson (1890–1973), businessman, knighted 1934
• William Johnstone, awarded the Military Cross and died of wounds in 1917
• MacGregor, awarded the Military Cross and permanently incapacitated