Hampden was originally settled as a residential community for workers at the mills that had sprung up along the Jones Falls; its first residents were in place well before the area was annexed to Baltimore City in 1889. Many of its residents came to the area from the hill country of Kentucky, West Virginia, and western Pennsylvania, due to the abundance of jobs the mills provided. This influx cemented the image of the neighborhood for the decades that followed as  working-class.

Beginning in the early 1990s, the neighborhood (conveniently located vis-a-vis Johns Hopkins and downtown) was discovered by artists and others, who began reclaiming the neighborhood.[who?] Many new residents were attracted by the creation of an artist studio and office space known as the Mill Centre, located in the southernmost region of Hampden between Falls Road and Mill Road. Over the past decade, housing prices in Hampden have skyrocketed and the area’s commercial center on a four-block stretch of West 36th Street, known as The Avenue, has seen trendy boutiques, restaurants, art galleries, a yoga studio, an upscale winebar, and assorted specialty shops occupy storefronts that had been either vacant or in a state of disrepair. The community of Wyman Park, as well as the actual park, are located to the east. The Woodberry station on the Baltimore Light Rail system is just on the other side of the Jones Falls Expressway and is within walking distance of much of the neighborhood. A new, high-end mixed-use development at Clipper Mill, directly in front of the Woodberry Light Rail station, has spurred additional economic activity in the area.