When his money was stolen, he worked as a mail carrier, riding between the Two Grey Hills, New Mexico trading post and Fort Defiance, Arizona, to earn enough to get back home.

'"[12] On a second trip two years later, he collected information on mining and brought home costumes and artifacts, including cowboy and aboriginal American clothing.

His early trips to the western United States inspired a period of images of cowboys and aboriginal Americans that dramatized the Old West.

[4] Upon returning to Chadds Ford, he painted a series of farm scenes for Scribner's, finding the landscape less dramatic than that of the West but nonetheless a rich environment for his art: "Everything lies in its subtleties, everything is so gentle and simple, so unaffected.

[15] Wyeth was very sociable, and frequent visitors included F. Scott Fitzgerald, Joseph Hergesheimer, Hugh Walpole, Lillian Gish, and John Gilbert.

[18] He also illustrated editions of Kidnapped (1913), Robin Hood (1917), The Last of the Mohicans (1919), Robinson Crusoe (1920), Rip Van Winkle (1921), The White Company (1922), and The Yearling (1939).

He did work for prominent periodicals, including Century, Harper's Monthly, Ladies' Home Journal, McClure's, Outing, The Popular Magazine, and Scribner's.

[citation needed] By 1914, Wyeth loathed the commercialism upon which he became dependent, and for the rest of his life he battled internally over his capitulation, accusing himself of having "bitched myself with the accursed success in skin-deep pictures and illustrations".

He complained of money men "who want to buy me piecemeal" and that "an illustration must be made practical, not only in its dramatic statement, but it must be a thing that will adapt itself to the engravers' and printers' limitations.

"[19] Wyeth also did posters, calendars, and advertisements for clients such as Lucky Strike, Cream of Wheat, and Coca-Cola, as well as paintings of Beethoven, Wagner, and Liszt for Steinway & Sons.

[21] His nonillustrative portrait and landscape paintings changed dramatically in style throughout his life as he experimented first with impressionism in the 1910s (feeling an affinity with the nearby "New Hope Group"), the principles of the divisionist painter Giovanni Segantini, then by the 1930s veering to the realistic American regionalism of Thomas Hart Benton and Grant Wood, painting with thin oils and, occasionally, egg tempera.

[22] Wyeth made four illustrations for a 1939 edition of Helen Hunt Jackson's Ramona, a novel about a Scottish-Native American orphan living in Southern California after the Mexican-American War.

The second illustration out of the four, depicting the tension between Ramona and her mother Señora Moreno, was found 80 years later in a Savers thrift store for $4 and sold for $191,000 at auction in 2023.

[24] In October 1945, Wyeth and his grandson (Nathaniel's son, whose name was also Newell) were killed when the automobile they were riding in was struck by a southbound Octoraro Branch freight train at a railway crossing over Ring Road near his Chadds Ford home.