The Wheeling National Heritage Area was created in 2000. The heritage area encompasses the central portion of Wheeling, particularly the part neighboring on the Ohio River. It includes a mixture of residential, commercial, entertainment, industrial, and government structures, with many buildings well over 100 years old. The heritage area's primary purpose is to foster economic development by exploiting Wheeling's natural, historical, and architectural assets. It is one of 24 national heritage areas in the United States, including the National Coal Heritage Area in southern West Virginia.

The ideas behind the Wheeling National Heritage Area were in large part generated by Harry Hamm, editor of the Wheeling News-Register, who authored the 1987 report "Wheeling 2000." The project was supported by Wheeling businessmen and organizations, Sen. Robert C. Byrd, Congressman Alan Mollohan, the National Park Service, and the state of West Virginia. National heritage areas are designated by Congress to recognize regions making an important contribution to the history and experience of America.

A key element of the plan was the formation of the Wheeling National Heritage Area Corporation, on June 13, 1994. The intent of the heritage plan was a rebirth of Wheeling as an important port of entry to the heartland by returning its face to the Ohio River. Most notably, more than $17 million dollars in public and private investment were used to renovate four abandoned historic structures along the waterfront. Among other accomplishments are the creation of the Wheeling Heritage Trail, the issuance of partnership grants for identifying and preserving Wheeling’s heritage, and the creation of a documentary on the LaBelle Nail Works.

The Wheeling National Heritage Area invested in the former Wheeling Stamping building, which is now Orrick’s Global Operations & Innovation Center. It has partnered in revitalizing the historic Capitol Theatre, built the award-winning riverfront amphitheater Heritage Port, and developed the Artisan Center, a renovated downtown industrial building. Wheeling Heritage also has spearheaded restoration efforts at Mt. Wood Cemetery, West Virginia's oldest, and played a key role in Wheeling’s 250th anniversary in 2019.

In 2016, the organization merged with Reinvent Wheeling, the city's Main Street program, to add programs focusing on business development, city planning, public art, and promotions.