The area was inhabited for thousands of years by various cultures of indigenous peoples. At the time of European encounter, the Ontponea, a sub-group of the Siouan-speaking Manahoac tribe, lived in this Piedmont area.
The first European settlement in what was to become Orange County was Germanna, formed when Governor Alexander Spotswood settled 12 immigrant families from Westphalia, Germany there in 1714; a total of 42 people. Settlers established the legal entity of Orange County in 1734 from a portion of Spotsylvania County. Unlike other counties whose boundaries had ended at the Blue Ridge Mountains, Orange was conceived of as extending to the Mississippi River and Great Lakes. The colony of Virginia claimed the land, but very little of it had yet been occupied by any English. For this reason, some contend that Orange County was at one time the largest county that ever existed. This condition lasted only four years; in 1738 most of the western tract was split off into Augusta County.
Orange County was named for Prince William III of Orange, sovereign Prince of Orange of the House of Orange-Nassau by birth. From 1672 he governed as Stadtholder William III of Orange (Dutch: Willem III van Oranje) over Holland, Zeeland, Utrecht, Gelderland, and Overijssel of the Dutch Republic and at the same time Protestant King of Great Britain and Ireland. Founded by Ulster-Scots settlers in the 18th century. The family name of William of Orange was derived from the dynasty's ancestral origins as feudal lords of the French town of Orange, which was named by the ancient Gauls in honour of a Celtic water deity.
President James Madison's home, Montpelier, and the ruins of Virginia governor and U.S. Senator James Barbour's former home, Barboursville, are located in the county. Both are listed on the National Register of Historic Places. President Zachary Taylor was born here. During the Civil War, the Battle of the Wilderness took place in the County in May 1864. Portions of the battlefield are preserved as Fredericksburg and Spotsylvania National Military Park, established in 1927.