Debris flows associated with rainstorms are a frequent and devastating hazard in the Southern Appalachians in the United States. Whereas warm-season events are clearly associated with heavy rainfall intensity, the same cannot be said for the cold-season events. Instead, there is a relationship between large (cumulative) rainfall events independently of season, and thus hydrometeorological regime, and debris flows. This suggests that the dynamics of subsurface hydrologic processes play an important role as a trigger mechanism, specifically through soil moisture redistribution by interflow. We further hypothesize that the transient mass fluxes associated with the temporal-spatial dynamics of interflow govern the timing of shallow landslide initiation, and subsequent debris flow mobilization. The first objective of this study is to investigate this relationship. The second objective is to assess the physical basis for a regional coupled flood prediction and debris flow warning system. For this purpose, uncalibrated model simulations of well-documented debris flows in headwater catchments of the Southern Appalachians using a 3-D surface–groundwater hydrologic model coupled with slope stability models are examined in detail. Specifically, we focus on two vulnerable headwater catchments that experience frequent debris flows, the Big Creek and the Jonathan Creek in the Upper Pigeon River Basin, North Carolina, and three distinct weather systems: an extremely heavy summertime convective storm in 2011; a persistent winter storm lasting several days; and a severe winter storm in 2009. These events were selected due to the optimal availability of rainfall observations; availability of detailed field surveys of the landslides shortly after they occurred, which can be used to evaluate model predictions; and because they are representative of events that cause major economic losses in the region. The model results substantiate that interflow is a useful prognostic of conditions necessary for the initiation of slope instability, and should therefore be considered explicitly in landslide hazard assessments. Moreover, the relationships between slope stability and interflow are strongly modulated by the topography and catchment-specific geomorphologic features that determine subsurface flow convergence zones. The three case studies demonstrate the value of coupled prediction of flood response and debris flow initiation potential in the context of developing a regional hazard warning system.