Denis George Mackail was born in Kensington, London to the writer John William Mackail and Margaret Burne-Jones, daughter of the painter Edward Burne-Jones. Educated at St Paul's School, Hammersmith, he went to Balliol College, Oxford, but failed to complete his degree through ill-health after two years.
His first work was as a set designer, notably for J.M. Barrie's The Adored One and George Bernard Shaw's Pygmalion (1914). The outbreak of World War I interrupted this promising start, however, and Denis, not fit enough for active service, worked in the War Office and the Board of Trade.
In 1917 he married Diana Granet, only child of the railway manager Sir Guy Granet, who was a director-general for railways in the War Office. The couple had two children, Mary (born 28 March 1919) and Anne (born 12 January 1922) and lived in Chelsea, London. It was the necessity of supporting his young family that led Denis to write a novel when office jobs became insecure after the end of the war.
With his novel published, his first short-story accepted by the prestigious Strand Magazine and the services of a literary agent, A. P. Watt, Denis was soon earning enough from his writing to give up office work. He published a novel every year from 1920 to 1938 and among his literary friends were P. G. Wodehouse and A. A. Milne.
During the 1930s Mackail lived at Bishopstone House, Bishopstone near Seaford, Sussex
As therapy from a nervous breakdown, Denis agreed to write the official biography of J.M. Barrie, which appeared in 1941. He went on to produce seven more novels and some books of reminiscences, but after the early death of his wife in 1949, he published no more and lived quietly in London until his death.
His sister was the novelist Angela Thirkell.