The area was initially settled in the late 1790s upon the arrival of brothers Joseph and Andrew Barnett,[6] as well as their brother-in-law Samuel Scott, who together established the first settlement at the confluence of the Sandy Lick and Mill Creeks in the area now known as Port Barnett. The first non-Native American settler of the land within the eventual town limits was Moses Knapp,[7] who built a log house at the confluence of North Fork Creek and Sandy Lick Creek (which form Redbank Creek) in 1801.[8][9]
The 105th Pennsylvania Infantry Regiment (also known as the "Wildcat Regiment") was a volunteer infantry regiment that served in the Union Army during the American Civil War and was raised by Amor A. McKnight of Brookville. The Regiment fought in several engagements, including Chancellorsville and Spotsylvania Court House.
Brookville's main source of economic development throughout the 19th century was the lumber industry. Brookville's many creeks and its connection to larger rivers (the Clarion to the north, which, like the Redbank, flows to the Allegheny) allowed for extensive construction of lumber mills along the watersheds and the floating of timber to markets in Pittsburgh. The town enjoyed great economic success during the late 19th and early 20th centuries, serving as home to several factories, breweries, an important railroad stop for local coal and timber, and briefly the Twyford Motor Car Company, which operated from 1905 to 1907 and produced the world's first four-wheel drive automobile.