In 1791, portions of Montgomery County, including Georgetown, were ceded to form the new District of Columbia, along with portions of Prince George's County, Maryland, as well as parts of Virginia that were later returned to Virginia.

In 1828, construction on the C&O Canal commenced and was completed in 1850. Throughout the 19th century, agriculture dominated the economy in Montgomery County, with slaves playing a significant role. In the 1850s, crop production shifted away from tobacco and towards corn. Montgomery County was important in the abolitionist movement, with slave Josiah Henson, who wrote about his experiences in a memoir which became the basis for Harriet Beecher Stowe's Uncle Tom's Cabin.

Until 1860, only private schools existed in Montgomery County. Initially, schools for caucasian students were built, and in 1872 schools for African-Americans were added.

In 1873, the Metropolitan Branch of the Baltimore & Ohio Railroad opened, with a route between Washington, D.C. and Point of Rocks, Maryland. The railroad spurred development at Takoma Park, Kensington, Garrett Park, and Chevy Chase.

On July 1, 1997, Montgomery County annexed a portion of Prince George's County, after residents of Takoma Park, which spanned both counties, voted to be entirely within the more affluent Montgomery County.

In October 2002, Montgomery County appeared in national headlines during the Beltway sniper attacks. There were five fatal shootings in 15 hours in Montgomery County. Of the fifteen shootings that took place, seven were located in Montgomery County.