In Hudson, he worked briefly at his father's tannery before opening a successful tannery of his own outside of town with his adopted brother.
In 1820, John Brown married Dianthe Lusk. Their first child, John Jr, was born 13 months later. In 1825, Brown and his family moved to New Richmond, Pennsylvania, where he bought 200 acres (81 hectares). He cleared an eighth of it and built a cabin, a barn, and a tannery. Within a year the tannery employed 15 men.
John Brown also made money raising cattle and surveying. He helped to establish a post office and a school. During this period, Brown operated an interstate business involving cattle and leather production along with a kinsman, Seth Thompson, from eastern Ohio.
In 1831, one of his sons died. Brown fell ill, and his businesses began to suffer, which left him in terrible debt. In the summer of 1832, shortly after the death of a newborn son, his wife Dianthe died.
On June 14, 1833, Brown married 16-year-old Mary Ann Day (April 15, 1817—May 1, 1884), originally of Meadville, Pennsylvania. They eventually had 13 children, in addition to the seven children from his previous marriage.