Tennallytown (now Tenleytown) is the second oldest neighborhood in the District. It was named after John Tennally, a local blacksmith. In 1790, Mr. Tennally established the first tavern in the area at Wisconsin Avenue and River Road , which provided food, drink, and lodging. The tavern served travelers between Frederick , Maryland and the port of Georgetown .

Area roads in the eighteenth and nineteenth centuries included River Road, Belt Road, Grant Road, Loughborough Road (now Nebraska Avenue), and Tennallytown Road (now Wisconsin Avenue). Tennallytown Road was also known as Tobacco Road, as Maryland tobacco was shipped along it to the ports in Georgetown . The oldest existing house in the neighborhood is The Rest, built in 1801. Other extant 19th century houses are found in the Grant Road Historic District.

Tennallytown was touched by two wars in the nineteenth century. In 1814, many District residents, including Dolley Madison, escaped into Maryland through Tennallytown when the British invaded Washington . Tennallytown was also the site of a Civil War fort, Fort Pennsylvania, later renamed Fort Reno, which was built on the highest point in Washington. Fort Reno was one of a ring of 26 forts built to protect the city from invasion. Washington was the most fortified city in the world at the time. It became known as "The Summit that saved the Union" due to its crucial role in repelling the confederate army's attack on Washington in 1864. President Lincoln reviewed the troops at this site. Confederate forces seeking to attack Washington approached Fort Reno , but changed course after coming under fire and instead attacked Fort Stevens , where they were defeated in the only military engagement in the District. After the war, the fort was dismantled and the site became an African-American residential area until the 1930s, when it became a federal park.

After the Civil War, Tennallytown was settled by tradesmen and merchants, such as carpenters, stonemasons, painters, grocers, and butchers. Farming continued to be a major occupation, and the area remained primarily rural for another 70 years. Shortly after the turn of the century, Tennallytown became known as Tenleytown. President Teddy Roosevelt was a frequent visitor, riding his horse from the White House. President Woodrow Wilson also visited Tenleytown during his White House years.

The arrival of the Sears Roebuck department store in 1941 brought modern times to Tenleytown. The building, now landmarked, was an early example of an “upside down building” because it had parking on the roof and the shoppers descended into the store on escalators. The Sears store was the beginning of modern commercial development on Wisconsin Avenue , and spurred the development of Tenleytown as an increasingly urban area.