James Patton, who came to America at age 17 and moved to North Carolina in 1793, started the settlement of Canogege (spelled "Conegoge" by George P. Donahoo).

The Rigdonite Mormon settlement at Greencastle only lasted a few years; some former Rigdon followers went to Utah to join Brigham Young, while William Bickerton, who had opposed Rigdon's move to Greencastle, would eventually reorganize the remaining Pennsylvania branch of the Latter Day Saint movement in Pittsburgh as the Church of Jesus Christ (Bickertonite).

Early in the Civil War, Greencastle and neighboring Franklin County communities raised the 126th Pennsylvania Infantry.

In the summer of 1863, the war touched close to home when Confederate General Robert E. Lee and his Army of Northern Virginia invaded southern Pennsylvania during the Gettysburg Campaign.

From mid-June to early July, those residents of Greencastle who had not fled to safety lived under Confederate rule.

On July 2, concurrent with the Battle of Gettysburg in neighboring Adams County, Captain Ulric Dahlgren's Federal cavalry patrol galloped into Greencastle's town square, where they surprised and captured several Confederate cavalrymen carrying vital correspondence from Richmond.

In 1902, Greencastle businessman Philip Baer began a tradition where the town holds a triennial social event known as "Old Home Week".

Every three years, Greencastle townspeople and former residents come together for one week in August in a town-wide reunion to reminisce and fellowship.

The present-day Methodist church has origins dating back to 1805 when Christian Newcomer conducted services in the area.

According to the United States Census Bureau, the borough has a total area of 1.6 square miles (4.1 km2), all land.

Originally, this was purchased with the intent of expanding the school, but the district decided instead to renovate and utilize the farm for student and community learning.

The GAYF utilizes the High Line Train Station to host clubs and youth groups such as Scouts BSA.