Some of the first documentation of early Middletown dates back to the late 18th century and is attributed to Dr. Peter Senseney and his wife Magdelen, two German settlers who had migrated from Pennsylvania.

[6] Belle Grove Plantation, about a mile southwest of Middletown, was first settled in about 1750, and its historic Federal-style manor house was completed in 1797.

Middletown was the site of numerous military operations in the American Civil War including the Battle of Cedar Creek, fought just south of the town.

The area where this battle occurred has been protected as part of the Cedar Creek and Belle Grove National Historical Park.

In 2012 the town of Middletown elected the youngest mayor in Virginia history at the age of 24, Charles Hamilton Harbaugh IV.

U.S. Route 11 (Main Street) runs through the center of Middletown and extends northeast-southwest, serving primarily as a local service road for nearby Interstate 81.

Exit 302 along I-81 connects with Reliance Road just east of the town limits, providing direct access to Middletown.

It interchanges with Interstate 66 just to the south of Middletown, which extends eastward to Washington, D.C. As of the census[3] of 2000, there were 1,015 people, 409 households and 280 families residing in the town.