He began painting portraits for a livelihood and descended the Mississippi to New Orleans, where for a time he taught drawing. From 1823 to 1828 his wife conducted a private school, in which he taught for a short time, in West Feliciana parish, La. In 1826 he went to Great Britain in search of a publisher and subscribers for his bird drawings, meeting with favorable response in Edinburgh and London. The Birds of America, in elephant folio size, was published in parts between 1827 and 1838, with engravings by Robert Havell,Jr. The accompanying text, called the Ornithological Biography (5 vol., 1831–39), was prepared largely in Edinburgh in collaboration with the Scottish naturalist William MacGillivray, who was responsible for its more scientific information. Extracts from Audubon's contributions, edited in 1926 by F. H. Herrick as Delineations of American Scenery and Character, reveal his stylistic qualities and furnish many pictures of American frontier life. Audubon worked on a smaller edition of his great work and also, in collaboration with John Bachman, began The Viviparous Quadrupeds of North America, which was completed by his sons Victor Gifford Audubon and John Woodhouse Audubon (plates, 30 parts, 1842–45; text, 3 vol., 1846–54).

During these years his home was on the Hudson River in the northern part of Manhattan island. While his drawings and paintings of bird life may not wholly satisfy both the critical artist and the meticulous scientist, their achievement in both areas is considerable. They remain one of the great achievements of American intellectual history and have gained wide popularity, having been reprinted many times.