This river was named by Oregon pioneer Lindsay Applegate, who prospected along its banks on his way to the California gold discoveries in 1949. Lindsay was one of three brothers who helped open the Southern Route off the Oregon Trail into the Willamette Valley in 1846. By the early 1850s, gold-seekers were pouring into the Applegate Valley and up its tributaries, including Williams Creek, resulting in a series of bloody clashes between them and the various bands of Applegate Athapascans who lived there. One of the strongest leaders of the Applegates at the time was Tecumtum, known to whites as Chief John or Old John, who would later gain notoriety as a stubborn resistor and crafty strategist during the Rogue River Wars to come.