Nannie Huddle was born in Whistler, Alabama, and educated in nearby Mobile. As a young girl she came to Austin, where she continued her study of art under Sister Florentine at St. Mary's Academy. In 1879 another of her teachers at St. Mary's was William Henry Huddle whom she married ten years later. Following her husband's death in 1892, Huddle studied at the Art Students League of New York. Her instructors in New York included William Merritt Chase, Marshall Fry, and Wayman Adams, and in Chicago the potter Susan Stuart Frackelton.
Huddle returned to Austin about 1900. She continued as a student and protege of Elisabet Ney and in 1901 began teaching at the Texas School for the Deaf; she retired about 1945. During World War I the Texas Legislature commissioned Huddle to paint a portrait of President Woodrow Wilson, which she reportedly executed after one sitting in the White House. Known for her paintings of wildflowers, Huddle is said to be one of the first Texas artists to paint fields of bluebonnets. She died in Austin.