Anthropogenic landscapes negatively impact stream habitats by altering hydrologic, sediment, and nutrient cycling regimes, thereby reducing or displacing populations of sensitive biota. The hellbender (Cryptobranchus alleganiensis) is an imperiled salamander endemic to eastern and central North American streams. Although once widespread, hellbender distributions have contracted and populations have declined in the past several decades. Hellbenders are considered indicators of stream quality; however, few studies have empirically linked hellbender presence to stream habitat or water-quality. We examined the ability of catchment-scale land-use and local physical and chemical habitat parameters to predict hellbender occurrence in an Appalachian headwater river drainage. Generalized linear models revealed that water-quality, local habitat, and catchment land-use are informative predictors of hellbender site occupancy. Because broad-scale land-use changes likely affect hellbender populations at multiple levels, management and conservation should focus on protecting streams at the catchment scale. In this system, ex-urban development appears to be the primary threat to hellbenders. However, threats to hellbender populations may be mitigated by management regulations targeting economically important outdoor recreational activities including trout fishing as well as existing streamside development guidelines.