Prior to the Treaty of Hopewell, the land that now is occupied by Hendersonville was settled by Cherokee tribes. Following this treaty, white settlers entered the region, eventually taking the land of what is now Henderson County in full from the original inhabitants. Poor trade links still restricted economic and demographic growth in the region, until the development of the Buncombe Turnpike, completed in 1827.

Wealthy low-country planters started to migrate to the area, building summer homes and bringing lots of money with them. In response to this population growth, Henderson County was split off from Buncombe County and founded in 1838.Judge Mitchell King owned 1,000 acres (4.0 km2), of which he donated 50 acres for the establishment of the town of Hendersonville.

He used some of the enslaved African Americans he owned as workers to lay out its 100-foot-wide (30 m) Main Street.Chartered in 1847 as the county seat of Henderson County (formed 1838), Hendersonville is traditionally known as "The City of Four Seasons". The town has a well-preserved Main Street and adjoining downtown areas with many restaurants, antique shops and boutiques in buildings that housed key local businesses until the mid-1980s.

At that point some businesses moved to suburban or highway locations, or were put out of business by big box competition. The town's architecture reflects the late 19th and early 20th centuries. Much downtown revitalization has occurred since the early 1990s. Larger stores have been developed almost entirely along the commercial strips extending outward from the downtown along U.S.

Highway 64 east and U.S. Highways 176 and 25. There are historic neighborhoods outside the Main Street corridor, including the 5th Avenue neighborhood on the city's west side and the Druid Hills neighborhood north of downtown. Depressed areas are found along the city's east side, but redevelopment efforts are underway in the historic commercial district along 7th Avenue East. The architectural focus of the downtown area is the historic Henderson County Courthouse, completed in 1905 and completely renovated in 2008.

The newly restored City Hall (erected 1924) and the modern Henderson County Courthouse (1995) are also located downtown. The largest street festival of the Hendersonville calendar is the annual North Carolina Apple Festival, culminating in the Apple Parade that regularly draws up to 50,000 spectators.

Main Street is home to other festivals and special activities throughout the year. High schools in the city and surrounding area include Hendersonville High School, West Henderson High School, North Henderson High School, and East Henderson High School. On December 5, 2020, during a fall surge in the COVID-19 pandemic in the United States, the First Baptist Church hosted a holiday concert with two performances, despite advice to postpone events with crowds.

In less than two weeks, 75 cases of the virus were traced to people who performed or attended the church events. It was characterized as a superspreader event, with a total of 97 cases by December 22. Until then Henderson County had recorded about 4,600 cases of COVID-19 and 89 deaths since the start of the pandemic in March.

No deaths were immediately attributed to the church event, as the illness takes time to develop.