Over-the-Rhine is believed to be the largest, most intact urban historic district in the United States. Because of its size, Over-the-Rhine has several distinct districts. OTR is bisected by Liberty Street. The Northern Liberties and the Brewery District are north of Liberty Street. South of Liberty are the Gateway Quarter and Pendelton.

Over-the-Rhine has been praised for its collection of historic architecture. The New York Times described the neighborhood as having "a scale and grace reminiscent of Greenwich Village in New York." Its architectural significance has also been compared to the French Quarter in New Orleans and the historic districts of Savannah, Georgia and Charleston, South Carolina. When Arthur Frommer, founder of the Frommer's travel guides, visited Over-the-Rhine he described it as the most promising urban area for revitalization in the United States, and claimed that its potential for tourism "literally could rival similar prosperous and heavily visited areas."