Born in Adelaide, Boothby was the son of pastoralist Thomas Wilde Boothby M.P. and his wife Mary Agnes, nee Hodding. Boothby's grandfather, Judge Benjamin Boothby, was removed from the South Australian Supreme Court Bench in 1867. Boothby's mother took her three sons to England in 1875 and he was educated at the Priory School, Salisbury, and at Lord Weymouth School, Warminster in Wiltshire. Boothby returned to Adelaide when he was sixteen and worked in the office of the Town Clerk of Adelaide before becoming private secretary to Mayor Lewis Cohen in 1890.
At the age of twenty, Boothby was writing short stories that appeared in London magazines. He also wrote plays that were performed in Adelaide theatres including a melodrama, The Jonquille, at the Theatre Royal on 14 and 15 August 1891. After its failure, he travelled with a friend, Longley Taylor, through the Far East, the Pacific Islands, New Guinea and Indonesia before making a journey on horseback and by buggy, boat and train from North Queensland to Adelaide. Boothby wrote about their travel experiences in On the Wallaby or Through the East and Across Australia.
He returned to England in 1894. His first novel, In Strange Company, was published that year, to be praised by the critics but not by the reading public. The character Claude de Carnyon in Love Made Manifest (1899) revealed much about Boothby's own ambitions to succeed as a writer. In the early years of the twentieth century Boothby occupied a place not unlike that held by Edgar Wallace twenty-five years later. Once successfully writing, Boothby lived at Winsley Lodge, a mansion in Watkins Road, Bournemouth with his wife and three children. Well before Edgar Wallace was supposedly pioneering the use of a dictaphone by authors, Boothby was dictating his thrillers into a phonograph and passing the wax cylinders to secretarial staff to be transcribed. He would then revise the rough drafts and send them back for fair copies to be typed. Sales of his work as magazine serials, followed by large print runs as books, enabled Boothby to earn an income of twenty thousand pounds a year. His method of working left ample spare time for social engagements and for his hobbies of breeding racehorses, dogs and exotic fish.
Rudyard Kipling, whom Boothby had met in Adelaide in 1891, had been friend and mentor in his career. In Guy Boothby: His Life and Work (1982), Paul Depasquale quotes Kipling as saying that he 'liked and respected [Boothby] immensely' (p. 117). Kipling is also quoted in Ward, Lock's catalogue included as endmatter in Farewell, Nikola (1901): 'Boothby has come to great honours now. His name is large upon hoardings, his books sell like hot cakes, and he keeps a level head through it all.' When Boothby died from pneumonia in England at the age of thirty-seven, he had written nearly fifty novels in ten years. H.A. Lindsay, writing about Boothby for the Bulletin in 1960, entitled the article 'Our First Successful Novelist', although few of his novels had an Australian setting. Many of his short stories were set in or around Australia.
He was the brother of Ben Boothby