The daughter of Thomas and Mary Ann (née Burton) Campbell, Mary trained as a nurse before marrying Billy Hughes at the age of 37 on 26th June 1911 at Christ Church, South Yarra in Victoria. They had one daughter, Helen, born 11th August 1915, who passed away, aged 21, in a London nursing home.

Fitzhardinge, in his biography of Billy Hughes in the Australian Biographical Dictionary advises that Dame Mary, "by her social gifts, tact and management, gave Hughes the domestic background he always lacked and provided precisely the feather-bedding that his restless activity and frail physique required."

The Hughes' marriage was not always happy. Dame Mary did not get on with Billy's children from his previous relationship with Elizabeth Cutts, who had passed away in 1906. She was also more frivolous with money than Hughes would have liked. Nevertheless Dame Mary was his constant companion, accompanying her husband during his parliamentary sessions to Melbourne and on domestic and overseas trips.
It was during the overseas trips at the time of the First World War that Dame Mary became interested in the welfare of Australian servicemen and visited camps and hospitals in Britain, France and Australia. The honour of Dame Grand Cross of the Order of the British Empire was conferred on her, in the New Years honours of 1922, for her charitable and war effort work.

After the war, Dame Mary continued with her charity work and became president of the Rachel Forester Hospital for Women and Children in Sydney in 1925. She was also an advocate for women's rights. Dame Mary outlived her husband by six years. After Billy passed away, on 28 October 1952, she stayed initially at their Lindfield property. Then in September 1955 she moved to live with her niece, Miss Edith Hayes.

Dame Mary Hughes died at the age of 83, at 8.30 p.m. on 2nd April 1958, at her niece's home in Double Bay. Her funeral service was held on Saturday 5 April at 10 a.m. at St Andrew's Cathedral, George Street, Sydney. She was interred in the Church of England section of the Marquarie Park Cemetery (incorporating Northern Suburbs Cemetery), with her husband and next to her daughter.