Unlike most portrait daguerreotypists of the mid-19th century—who were often more concerned with the quantity of their sales than with the quality of their portraits—Southworth and Hawes avoided contrived poses and painted backdrops. Instead, they gave each customer personal attention, making spontaneous portraits that revealed the personality of the sitter. For example, Lemuel Shaw (Shaw, Lemuel), then chief justice of the Massachusetts Supreme Court, was captured under a shaft of light that brought out rugged features that gave some sense of his dominant character. Southworth and Hawes were known for such creative use of light, which was in marked contrast to the bright, unflattering light then prevalent among daguerreotypists. They also developed methods that reduced exposure time, so as to avoid the stiff poses seen in most portraits of the time. The high quality of the work of Southworth and Hawes attracted many of the most prominent Americans of the day to their studio, including Senators Daniel Webster (Webster, Daniel) and Henry Clay (Clay, Henry) and the writer Harriet Beecher Stowe (Stowe, Harriet Beecher). The two men also made daguerreotypes of landscapes, cityscapes, and scenes that were not then accepted as proper subjects of photography, such as hospital operating rooms.

In 1849 Southworth went to California in a futile attempt to find gold. When he returned to Boston, his failing health prevented him from working actively. In 1861 he ended his partnership with Hawes, who continued to photograph independently until his death.