He formed a partnership with brother-in-law James Disher as wine merchants and as "Disher & Milne", in July 1846, purchased the Hindley Street wine and spirit business of Patrick Auld, who was returning to England.

In 1857 Milne sold his distillery and was elected to the South Australian House of Assembly as one of the members for Onkaparinga.

Milne served as commissioner of Crown Lands and immigration in the ministry of John Baker from 21 August to 1 September 1857, under Richard Hanson from 5 July 1859 to 9 May 1860, under Henry Ayers from 22 July to 4 August 1864 and under James Boucaut from 28 March 1866 to 3 May 1867.

[1][4] Milne transferred to the Legislative Council in 1869 and was elected its president in 1873, serving until his retirement in 1881.

[5] William Milne married Eliza Disher (c. 1818 – 17 August 1912), daughter of John Disher of "Byethorne", Nairne, South Australia in 1842; they later lived at "Sunnyside", Glen Osmond; they had a large family: Eliza Milne's sister Margaret "Minnie" Disher (died 11 April 1900) married James Johnston (1818 – 12 April 1891), one of the Johnston brothers of Oakbank.