He married, Mona Brady, daughter of J.P. Brady, on 28 August 1958 in Clonmel, Tipperary. The wedding was followed by a reception at the Galtee Hotel, Cahir which was attended by various notables including Rev. Father J.J. Hampson, President of Blackrock College. Their first child, Mary Hanafin, was born in June 1959, followed by John Hanafin in September 1960.
Des Hanafin operated the Anner Hotel in Thurles during the 1960s, while initially successful, the business failed in 1967. Mary Hanafin later blamed the failure on her father's excess drinking.
Des Hanafin's first attempt to become elected to public office proved unsuccessful. In 1953, Hanafin sought to be co-opted to fill the vacancy on North Tippeary County Council created by the death of his father, John Hanafin. In the event councillors co-opted a Labour Party nominee, Michael Treacy, by eleven votes to seven.
He was elected a member of North Tipperary County Council in 1955, polling 934 first preference votes. He was subsequently elected Chairman of the County Council in 1956 with the support of Clann na Poblachta representatives.
Hanafin was re-elected to North Tipperary County Council in 1960, polling 797 first preference votes. In 1961, he voted against the Fianna Fail nominee for Chair of the County Council, Thomas F. Meagher and in favour of the Clann na Poblachta nominee, Michael F. Cronin, who was elected by 10 votes to 9. In 1964, he controversially voted in favour of Jeremiah Mockler, "a former school mate", who was elected by 10 votes to 9 to the office of Rate Collector for Borrisokane.
He held the seat until 1985. He was first elected to Seanad Éireann in 1965 and retained his seat until the 1993 Seanad Elections at which he lost his seat by one vote. He regained his seat at the 1997 Elections and retired from politics in 2002. He unsuccessfully contested the Dáil elections of 1977 and 1981. He was a chief fundraiser of the Fianna Fáil party for many years.
Since retiring from the Seanad in 2002, Hanafin as occasionally made interventions concerning social issues. In May 2015, he accused equality campaigners in the Marriage referendum of spreading a "palpable climate of fear".