Lofting was born in Maidenhead, England, to English and Irish parents. His early education was at Mount St Mary's College in Sheffield, after which he went to the United States in 1904, completing a degree in civil engineering at the Massachusetts Institute of Technology. He studied at London Polytechnic. He traveled widely as a civil engineer, in Canada, on the Lagos Railway, and Railways of Havana, Cuba. In 1912, he married Flora Small; they had two children. He enlisted in the Irish Guards to serve in World War I. Not wishing to write to his children of the brutality of the war, he wrote imaginative letters that were the foundation of the successful Doctor Dolittle novels for children. Seriously wounded in the war, he moved with his family to Killingworth, Connecticut in the United States, in 1917. He served in the British Ministry of War Information. His first wife died in 1927, and second wife in 1928. He married Josephine Fricker, in 1935; they had a son named Christopher, who was the executor of his literary estate.

For years it was a constant source of shock to me to find my writings amongst 'juveniles,'" Lofting reported. "It does not bother me any more now, but I still feel there should be a category of 'seniles' to offset the epithet.

Hugh Lofting's doctor from Puddleby-on-the-Marsh who could speak to animals first saw light in the author's illustrated letters to children, written from the trenches during World War I when actual news, he later said, was either too horrible or too dull. The stories are set between the 1820s and 1840s. The Story of Doctor Dolittle: Being the History of His Peculiar Life at Home and Astonishing Adventures in Foreign Parts Never Before Printed (1920) began the series. The sequel, The Voyages of Doctor Dolittle (1922), won Lofting the prestigious Newbery Medal. Eight more books followed, and after Lofting's death two more volumes, composed of short unpublished pieces, appeared. The series has been adapted for film and television many times, for stage twice, and for radio.

The Story of Mrs Tubbs (1923) and Tommy, Tilly, and Mrs. Tubbs (1936) are picture books aimed at a younger audience than the Doctor Dolittle books. They concern the titular old woman, her pets (whom she can talk to) and the animals who help her out of trouble.

Porridge Poetry (1924) is the only non-Dolittle work by Lofting still in print; it is a light-hearted, colourfully illustrated book of poems for children.

Noisy Nora (1929) is a cautionary tale about a girl who is a noisy eater. The book is printed as if hand-written, and the many illustrations often merge with the text.

The Twilight of Magic (1930) is, by contrast, aimed for older readers; it is set in an age when magic is dying and science beginning. This work is the only one of Lofting's books to be illustrated by another person (Lois Lenski).

Victory for the Slain (1942) is Lofting's only work for adults, a single long poem in seven parts about the futility of war; the refrain "In war the only victors are the slain" permeates the poem. It was published only in the United Kingdom.