Frederick County was named for Frederick Louis, Prince of Wales and eldest son of George II. It was formed from Orange County in 1738, but the county government was not organized until 1743. Part of Augusta County was added later.

The Society of Friends Crooked Run Meeting was located near the village of Nineveh about 13 miles south of Winchester in what was then Frederick County but is today Warren County. A meeting for worship was established in 1758 or earlier. A meeting house was built and a preparative meeting established in 1760. In 1781 Hopewell Monthly Meeting was divided and a new monthly meeting set up under the name of Crooked Run Monthly Meeting, which was ordered to meet alternately at Crooked Run and Centre. The first session of the new monthly meeting was held 5th month 29, 1782. Crooked Run Monthly Meeting was laid down 5th month 18, 1807 and the members joined to Hopewell Monthly Meeting as Crooked Run Preparative Meeting. The preparative meeting was laid down 10th month 5, 1810. Inferior meetings mentioned in the records as being embraced in Crooked Run Monthly Meeting include Crooked Run, Centre, Smith's Creek, Stafford, Southland, Mt. Pleasant and Culpeper. In 1812 selling the house was considered, but it was still held in 1828, though in bad condition. The site is now occupied by the Nineveh Presbyterian Church.

The Virginia General Assembly passed a law in November 1766 exempting Quakers from appearing or mustering at the private or general musters of militia of their respective counties. The law also required that the commanding officer of the militia company keep a list of all male persons of the people called Quakers above the age of eighteen years and under the age of sixty years. Any person on this list was required to provide a substitute at such time that the militia was called into official action or face a fine of ten pounds. Additionally, any person claiming to be a Quaker had to produce a testimonial from the monthly meeting to which he belonged certifying that he really was a Quaker and was not just trying to shirk militia duty.