Eventually, conflicts with neighboring tribes and European settlers forced the migration of the Piscataway from their ancestral homelands of Prince George's County to Heater's Island around 1699, though their population was severely decreased by an outbreak of smallpox in 1704.

"[5] The Nelson Family retained their status as prominent landholders in Point of Rocks in the early-18th century, developing several plantations on which tobacco was grown.

The village became a temporary terminus for both the C&O Canal and the B&O Railroad in 1828 when the companies went to court to determine which would control the right of way through the narrow passage between the Potomac River and Catoctin Mountain immediately west of Point of Rocks.

After six years of court battles, the companies agreed to compromise and share the right of way, the B&O Railroad eventually constructing a tunnel through the mountain to broaden its lines through the narrow water gap.

[7] With the construction of the C&O Canal and the B&O Railroad and its strategic location on the Potomac River, Point of Rocks was poised to become a regional transportation hub and center of industrial activity.

[8] From the earliest days of European settlement in Point of Rocks, forced labor through indentured servitude and enslavement of African Americans drove the local economy.

Nearby Licksville, a small community located near Noland's Ferry crossing the Potomac River was the site of an active slave market.

[11] The Loudoun Rangers spent most of 1862 and 1863 fighting alongside Cole's Maryland Cavalry (the First Potomac Home Brigade) to protect the C&O Canal and the B&O Railroad from frequent Confederate raids.

While being transported to Frederick for trial, a mob swarmed the train as it approached the station in Point of Rocks, removed Carroll from police custody, and hanged him in an adjacent field.

An ongoing Federal Emergency Management Agency program to reduce flood insurance payouts has resulted in the purchase and demolition of a large portion of structures on the lowest-lying properties.

Point of Rocks is located in southern Frederick County, on the north bank of the Potomac River, and is bordered to the west by U.S. Route 15, which here runs along the eastern base of Catoctin Mountain.