Francis was born in Pembrokeshire, Wales. Some sources report his birthplace as the inland town of Lawrenny, but at least two of his obituaries stated his birthplace as the coastal town of Tenby. His autobiography says that he was born at his maternal grandparent's farm at Coedcanlas on the estuary of the River Cleddau, roughly a mile north-west of Lawrenny. He was the son of a jockey and stable manager and he grew up in Berkshire, England. He left school at 15 without any qualifications, with the intention of becoming a jockey and became a trainer in 1938. During World War II, he served in the Royal Air Force, piloting fighter and bomber aircraft, including the Spitfire and Hurricane. In October 1945, he met Mary Margaret Brenchley (17 June 1924 - 30 September 2000), whom he married in June 1947 in London; they had two sons, Merrick and Felix (born 1953). In the 1980s, Francis and his wife moved to Florida; in 1992, they moved to the Cayman Islands, where Mary died of a heart attack. In 2006, Francis had a heart bypass operation; in 2007 his right leg was amputated. He died of natural causes on 14 February 2010 at his Caribbean home in Grand Cayman, survived by both sons.

After leaving the RAF in 1946, Francis became a celebrity in the world of British National Hunt racing. He won over 350 races, becoming champion jockey in the 1953—54 season.

From 1953 to 1957 he was jockey to Queen Elizabeth the Queen Mother. In 1957 he was forced to retire from racing as the result of a serious fall. His most famous moment as a jockey came while riding the Queen Mother's horse, Devon Loch, in the 1956 Grand National when the horse inexplicably fell when close to winning the race.

Francis wrote more than 40 international bestsellers. His first book was his autobiography The Sport of Queens (1957) which led to him becoming the racing correspondent for London's Sunday Express newspaper, remaining in the job for 16 years. In 1962 he published his first thriller Dead Cert, set in the world of racing. Subsequently he regularly produced a novel a year for the next 38 years, missing only 1998 (during which he published a short-story collection). Although all his books were set against a background of horse racing, his heroes held a variety of jobs from artist (In the Frame and To the Hilt) to private investigator (Odds Against, Whip Hand, Come to Grief, Under Orders-- all starring injured ex-jockey Sid Halley).

Francis is the only three-time recipient of the Mystery Writers of America's Edgar Award for Best Novel, winning for Forfeit in 1970, Whip Hand in 1981, and Come To Grief in 1996. Britain's Crime Writers Association awarded him its Gold Dagger Award for fiction in 1979 and the Cartier Diamond Dagger lifetime achievement award in 1989. In 1996 he was given the Mystery Writers of America Grand Master Award, the highest honour bestowed by the MWA. He was awarded a Commander of the British Empire (CBE) in 2000. In 2003 he was honoured by being awarded the Gumshoe Awards' Gumshoe Lifetime Achievement Award.

Many of Francis' books are featured in volumes of Reader's Digest Condensed Books.

Francis' manager (and co-author of his later books) was his son Felix Francis, who left his post as teacher of A-Level Physics at Bloxham School in Oxfordshire in order to work for his father and who was the inspiration behind a leading character in the novel Twice Shy. His other son Merrick, formerly a racehorse trainer, later ran his own horse transport business, which inspired the novel Driving Force.

He was elected in 1999 a Fellow of the Royal Society of Literature