Eliza Burnell introduced her 15-year-old daughter to Joseph Lyons, a rising Tasmanian Labor Politician. On 28 April 1915, the two married at Wynyard, Tasmania; she was 17 and Lyons was 35. Enid had been brought up a Methodist but became, at Lyons' request, a Roman Catholic. They would have twelve children, one of whom died in infancy.

Lyons was born in Smithton, Tasmania. She grew up in various small towns in northern Tasmania, and trained as a schoolteacher. At the age of 17, she married Politician Joseph Lyons, who was almost 18 years her senior. They would have twelve children together, all but one of whom lived to adulthood. As her husband's career progressed, Lyons began assisting him in campaigning and developed a reputation as a talented public speaker. In 1925, she became one of the first two women to stand for the Labor Party at a Tasmanian state election. She followed her husband into the new United Australia Party (UAP) following the Labor split of 1931.

In 1931 Joseph Lyons left the Labor Party and joined the United Australia Party (UAP), becoming prime minister at the subsequent election. Enid Lyons was made a Dame Grand Cross of the Order of the British Empire (GBE) in the Coronation Honours of 1937. Joseph Lyons died in 1939, aged 59, the first Australian prime minister to die in office, and Dame Enid returned to Tasmania. She bitterly resented Joseph Lyons's successor as leader of the UAP, Robert Menzies, who had, she believed, betrayed her husband by resigning from the cabinet shortly before Joseph's death.

After her husband became prime minister in 1932, Lyons began living at The Lodge in Canberra. She was one of the best-known prime minister's wives, writing newspaper articles, making radio broadcasts, and giving open-air speeches. Her husband's sudden death in office in 1939 came as a great shock, and she withdrew from public life for a time. At the 1943 federal election, Lyons successfully stood for the UAP in the Division of Darwin. She and Senator Dorothy Tangney became the first two women elected to federal parliament. Lyons joined the new Liberal Party in 1945, and served as Vice-President of the Executive Council in the Menzies Government from 1949 to 1951 – the first woman in cabinet. She retired from parliament after three terms, but remained involved in public life as a board member of the Australian Broadcasting Commission (1951–1962) and as a social commentator.

At the 1943 election Dame Enid Lyons narrowly won the Division of Darwin in north-western Tasmania for the UAP, becoming the first woman in the House of Representatives. Her Labor opponent, who received more primary votes than she did, was the Future Tasmanian Premier Eric Reece. At the same election, Dorothy Tangney was elected as a Labor Senator for Western Australia, the nation's first woman Senator. In 1945 the UAP became the Liberal Party of Australia.

On 23 August 1944, Lyons was one of four speakers in a debate on population which became the Australian Broadcasting Commission's "largest controversy during the war years" Lyons devoted a chapter to this Australian Broadcasting Corporation debate in her 1972 autobiography, calling it 'one of the most disturbing experiences I was to know as a member of parliament'. Her fellow debaters were Norman Haire, Jessie Street and the Economist Colin Clark.

By the time she was elected to parliament in her own right, there was very little left of her Labor ties. Her speeches in parliament generally espoused traditional views on the family and other social issues. In 1949 the Liberals came to power under Menzies' leadership. The frosty personal relations between Menzies and Dame Enid thawed slightly when Menzies gave her the role of Vice-President of the Executive Council. This was a largely honorary post which gave her a seat in cabinet but no departmental duties. Nevertheless, her health declined under the strain of regular travel between Canberra and Tasmania, and she retired from parliament prior to the 1951 election.

In retirement, Dame Enid's health recovered. She was a newspaper columnist (1951–54), a commissioner of the Australian Broadcasting Corporation (1951–62), and remained active in public life promoting family and women's issues. She published three volumes of memoirs, which embarrassed the Liberal Party by reviving her complaints about Menzies' 1939 behaviour towards her husband.

Lyons was made a Dame of the Order of Australia (AD) on Australia Day 1980, the second woman to receive this honour after Alexandra Hasluck. She was the first Australian woman to receive damehoods in different orders. She died the following year and was accorded a state funeral in Devonport, Tasmania, before being buried next to her husband at Mersey Vale Memorial Park.

An informal political faction of the Liberal/National opposition parties called the Lyons Forum was formed in 1992. The group's name alluded to Lyons' maiden speech to the House of Representatives. The faction was considered to be defunct in 2004.

Lyons first fell pregnant a few months after her marriage, but miscarried just after her 18th birthday. She suffered a second miscarriage the following year, and in her memoirs recounted having to watch on as a nurse threw the remains of the foetus into a bedside fireplace. She was told by doctors that she would never be able to have children, but in fact went on to give birth to twelve – the first born when she was 19 and the last born when she was 36. Her subsequent pregnancies went relatively smoothly, with the except of a third miscarriage in 1926; she had to carry the dead foetus for three months before it could be removed. All but one of her children survived to adulthood, and all those who did out-lived her. Her son Garnet, born in 1924, died from meningitis at the age of 10 months. Another son, Barry, was born with achondroplasia.