As a painter of portraits, figures, animals, and landscapes, he enjoyed a certain prominence during his lifetime,[1] and his paintings are represented in major American art collections.

During the last third of his life, he worked together with his son, Gerald Handerson Thayer, on a book about protective coloration in nature, titled Concealing-Coloration in the Animal Kingdom.

[7] He met many emerging and progressive artists during this period in New York, including his future wife, Kate Bloede and his close friend, Daniel Chester French.

[7] In 1875, after having married Kate Bloede, he moved to Paris, where he studied for four years at the École des Beaux-Arts, with Henri Lehmann and Jean-Léon Gérôme,[5] and where the American artist George de Forest Brush became his closest friend.

Returning to New York, he established his own portrait studio (which he shared with Daniel Chester French), became active in the Society of American Painters, and began to take in apprentices.

He also made numerous portraits of the three remaining Thayer children, Mary, Gerald, and Gladys, and used them as models for symbolic compositions such as Angel (1887) and Virgin Enthroned (1891).

[12] After her father died, Thayer's wife lapsed into an irreversible melancholia, which led to her confinement in an asylum, the decline of her health, and her eventual death on May 3, 1891, from a lung infection.

For example, he is largely known as a painter of "ideal figures", in which he portrayed women as embodiments of virtue, adorned in flowing white tunics and equipped with feathered angel's wings.

Biographer Ross Anderson believed that in his mind "feminine virtue and aesthetic grandeur were inextricably linked"; Thayer felt that the press and even other artists contributed to the degradation of women by emphasizing their sexuality, rather than exalting their moral attributes.

He also had a profound influence on Dennis Miller Bunker, who, while not a formal pupil, was invited to paint alongside the older artist in 1886, and wrote "Thayer's the first great man I ever knew, and I can't quite get used to it.

"[22] In a letter to Thomas Wilmer Dewing (c. 1917, in the collection of the Archives of American Art,[23] Smithsonian Institution), Thayer reveals that his method was to work on a new painting for only three days.

[5] While he did not invent camouflage, he was one of the first to write about disruptive patterning to break up an object's outlines,[5] about distractive markings, about masquerade, as when a butterfly mimics a leaf (though here he was anticipated by Bates, Wallace, and Poulton), and especially about countershading.

Beginning in 1892, he wrote about the function of countershading in nature, by which forms appear less round and less solid through inverted shading, by which he accounted for the white undersides of animals.

[3] Thayer first became involved in military camouflage in 1898, during the Spanish–American War, when he and his friend George de Forest Brush proposed the use of protective coloration on American ships, using countershading.

[5] The two artists did obtain a patent for their idea in 1902, titled "Process of Treating the Outsides of Ships, etc., for Making Them Less Visible", in which their method is described as having been modeled on the coloration of a seagull.

As he aged, he suffered increasingly from panic attacks (which he termed "fright-fits"), nervous exhaustion, and suicidal thoughts, so much so that he was no longer allowed to go out in his boat alone on Dublin Pond.