The Prettyboy region is an area rich with history. Prior to the European colonists' arrival, a range of Native American peoples lived and hunted in the rolling forested hills. It is not known exactly which tribes lived there but it is believed that Shawnees , Massawomecks, Susquehannocks, and Delawares or Lenni Lenapi ranged through the area. It is also thought that northern Baltimore County was more of a hunting ground area rather than a living area.

The first settlers to come into the region were English and land was made available to them by land grants. In the western part of the Prettyboy Watershed, the English settlers were followed by Scots and people of German descent, including Pennsylvania Dutch. Route 30 was cut in the 1730's as a conveyance between Hanover, Pennsylvania and Fort Garrison in Maryland . This opened the region to commerce and settlement.

The towns of Manchester and Hampstead were early stagecoach stops for the new road. Early farmers grew tobacco on the surrounding lands, and an extensive cigar manufacturing business existed for a period of time in Manchester . Iron mining was another activity that was pursued north of Manchester in Melrose . During the Civil War, Union troops camped around the towns before heading to battle in Gettysburg .

Farther east in the watershed, in what is now northern Baltimore County , mills of various sorts were established to take advantage of the strong stream currents. The first paper used for money printed by the Continental Congress was printed at Hoffman Mills on the upper Gunpowder. Gunpowder was also manufactured in the region.

The most significant human-made feature in the watershed is Prettyboy Dam. Conceived in 1918, Baltimore City worked for six years in the 1920's to purchase the 7,380 acres of property that would become the City-owned Reservoir and surrounding forests. Construction started in 1930 aided by many able-bodied workers brought in by the Civilian Conservation Corps of the Depression. The Dam was completed in 1933.

Presently, the region is home to a number of active farmers with corn, soybeans and wheat as the predominant crops. Horse farms are becoming more prevalent especially in Baltimore County . Most residents commute to jobs in the Baltimore, Hanover and York region.