Hughesville is named for Jeptha Hughes, who purchased land from John Heap in 1816 and laid out the town of "Hughesburg" before selling the entire plot to Daniel Harrold in 1820. The town grew slowly around a gristmill that was constructed by Jacob Clayton. A tavern was built in 1820, and a general store followed ten years later. The first doctor in Hughesville, John W. Peale, arrived in 1828. Hughesville was incorporated as a borough on April 23, 1852. The first dentist opened an office in 1853 and the first lawyer settled in Hughesville in 1875.
Early industries in Hughesville were built to serve the farmers and citizens of eastern Lycoming County. They included a chair factory opened in 1829, a wagon shop in 1830, several distilleries, a sawmill and planing mill, and a furniture factory. Electricity was introduced to Hughesville in 1891 along with running water.