In Steubenville, Cole also began to explore landscape painting after gaining some rudimentary instruction in oil painting from a portrait painter named Stein.  In 1823, Cole went with his family to Pittsburgh, where he again became an assistant in his father's business and made landscape sketches in his free time.

Inspired by the landscapes of Thomas Doughty and Thomas Birch, which he saw at the Pennsylvania Academy during a stay in Philadelphia from 1823 to 1825, Cole became dedicated to a career as a landscape painter.  In Philadelphia, he began to consider the distinctive characteristics of American scenery, but it was not until he moved to New York in 1825 that he turned his thoughts to his art.

The works he produced after a sketching trip up the Hudson River in the summer of 1825 attracted the attention of New York's prominent artists and patrons.  From this time until the end of his career, Cole enjoyed fame as a pre-eminent American landscape painter, and created works that influenced a generation of native artists who followed his lead in focusing on the sublime beauty and grandeur of the country's wilderness scenery.

In 1829, Cole became one of the founding members of the National Academy of Design, and departed on a trip to Europe.  Traveling through England, France, and Italy, he viewed works by the Old Masters and contemporary artists and explored European landscape sites.  A second trip to Italy, from 1831 to 1832, inspired Cole with ideas of exploring high-minded and grand themes.  In landscape paintings he created on his return, he expressed the moral issues and lofty ideals that were usually the exclusive domain of history painters.

After his return to America, Cole settled in the town of Catskill, New York, but he remained active in the art scene of New York City, keeping ties with fellow artists and collectors.  Among his acquaintances was the New York merchant, Luman Reed, who commissioned him to create "The Course of Empire, 1836 "(New-York Historical Society), a five-canvas epic that depicts the cyclical development of a society from a savage wilderness to a grand and luxurious state, to a condition of corruption and destruction, and finally to dissolution.

In the years that followed, Cole created both naturalistic views and imaginary scenes invested with moral or literary meaning.  He rendered the two-canvas Gothic fantasy, "The Departure and The Return" (Corcoran Gallery, Washington, D.C.) in 1837 and the four-canvas religious allegory, "The Voyage of Life" (two versions, Munson- Williams-Proctor Institute, Utica, New York, and National Gallery of Art, Washington, D.C.) in 1840.  Other allegorical landscapes include "Dream of Arcadia", 1838"(Denver Art Museum) and "The Architect's Dream", 1840 (Toledo Museum of Art).

Despite the esteem with which Cole's allegorical works were regarded, his patrons preferred his identifiably American scenes.  Cole was disappointed at this preference, but over the course of his career, he had steadily improved his landscape technique as may be seen especially in the works he created following his return from his second European sojourn, which demonstrated the impact of his exposure to European sources.  Cole's pure landscapes demonstrate many of the principles and intellectual ideas reflected in his allegorical works.  He expressed a romantic viewpoint, finding symbolic meaning in nature.  As he wrote: "A scene is rather an index to feelings and associations."

In addition to his activities as a painter, Cole was a prolific poet, writer, and theorist.  He kept many journals and wrote poetry and essays, including his well-known tract on American scenery of 1835.