Harry Leslie Hoffman was born in Cressona, a small community in Pennsylvania's Schuylkill Valley. His mother was an amateur artist who encouraged her son to pursue a career in the arts. In 1893, Hoffman entered the School of Art at Yale University and studied with John Ferguson Weir, the son of Robert Walter Weir. After graduation in 1897, Hoffman moved to New York to continue his studies at the Art Students League. He also traveled to Paris and took classes at the Académie Julien.

A man with strong academic art training, Harry Hoffman was judged by his peers to have done best with his landscapes when he painted what he saw and set aside the theories. He studied in Paris, worked at Yale University with John Ferguson Weir, and was a student at the Art Students League with Frank DuMond. But Willard Metcalf had the strongest influence, encouraging Hoffman to paint in the style of impressionism.

In the summer of 1902, Hoffman attended the Lyme Summer School of Art, in the town of Old Lyme on the Connecticut coast. He stayed at the Florence Griswold House, returning for many subsequent summers. At one point, when he was exceptionally low on money, he nearly became a professional baseball player, but was dissuaded by his painter friends.

In 1905, Hoffman settled in Old Lyme and worked as a full member of the artist colony. He was particularly influenced by Willard Leroy Metcalf, an Impressionist also working in Old Lyme. Fellow artists later fondly recalled Hoffman's antics at the Griswold house, which included playing the flute and banjo, tap-dancing, singing humorous songs, and performing magic tricks. In 1910 Hoffman married another Old Lyme artist named Beatrice Pope, and the couple had one child in 1921.

Hoffman and his wife often escaped New England during the harsh winter months. In the winters of 1914 and 1915 he traveled to Savannah, Georgia with fellow Old Lyme artist William Chadwick. Hoffman depicted urban genre scenes around the city and was inspired by the soft hazy light created by the tropical climate. Hoffman's Savannah paintings feature loose, Impressionistic brushwork and vibrant, saturated colors. In 1916, he visited the Bahamas and became interested in seascapes and underwater scenes. During the early twenties, Hoffman accompanied renowned naturalist William Beebe as a staff artist on expeditions to the Galapagos Islands, British Guiana, and Bermuda.

He married Beatrice Pope from East Orange, New Jersey, who was also staying at the Griswold House, and they lived in Old Lyme. In the 1920s, he had a reputation for his underwater life paintings, having made a bucket with a glass bottom that he floated on the water for special vantage points. Intrigued by the many colors he found in the ocean, he accompanied the naturalist William Beebe on research trips to the Galapagos Islands, Bermuda, and British Guiana.

He was awarded a gold medal at the Panama Pacific Exposition in 1915 and won the Eaton Prize, bestowed by the Lyme Art Association in 1924. His work is now located in private and permanent collections throughout the United States. In 1930, he was elected an Associate of the National Academy of Design. He was also very helpful to Florence Griswold in her old age when she was about to lose her house. Successfully avoiding that loss, he served as the treasurer and fund raiser of monies to save it as a home during her lifetime and as a museum when she died.

In addition to his long painting career, Hoffman was a writer, actor, and musician. He was active in the historic preservation of the Florence Griswold House, the intellectual center of the Old Lyme Colony, as a museum. Hoffman lived to be ninety-two years old and died at Old Lyme, Connecticut, on March 1966.