This research was designed to provide an understanding of physical wind mechanisms within the complex terrain of the Great Valley of Eastern Tennessee to assess the impacts of regional air flow with regard to synoptic and mesoscale weather changes, wind direction shifts, and air quality. Meteorological data from 2008–2009 were analyzed from 13 meteorological sites along with associated upper level data. Up to 15 ancillary sites were used for reference. Two-step complete linkage and K-means cluster analyses, synoptic weather studies, and ambient meteorological comparisons were performed to generate hourly wind classifications. These wind regimes revealed seasonal variations of underlying physical wind mechanisms (forced channeled, vertically coupled, pressure-driven, and thermally-driven winds). Synoptic and ambient meteorological analysis (mixing depth, pressure gradient, pressure gradient ratio, atmospheric and surface stability) suggested up to 93% accuracy for the clustered results. Probabilistic prediction schemes of wind flow and wind class change were developed through characterization of flow change data and wind class succession. Data analysis revealed that wind flow in the Great Valley was dominated by forced channeled winds (45–67%) and vertically coupled flow (22–38%). Down-valley pressure-driven and thermally-driven winds also played significant roles (0–17% and 2–20%, respectively), usually accompanied by convergent wind patterns (15–20%) and large wind direction shifts, especially in the Central/Upper Great Valley. The behavior of most wind regimes was associated with detectable pressure differences between the Lower and Upper Great Valley. Mixing depth and synoptic pressure gradients were significant contributors to wind pattern behavior. Up to 15 wind classes and 10 sub-classes were identified in the Central Great Valley with 67 joined classes for the Great Valley at-large. Two-thirds of Great Valley at-large flow was defined by 12 classes. Winds flowed on-axis only 40% of the time. The Great Smoky Mountains helped create down-valley pressure-driven winds, downslope mountain breezes, and divergent air flow. The Cumberland Mountains and Plateau were associated with wind speed reductions in the Central Great Valley, Emory Gap Flow, weak thermally-driven winds, and northwesterly down sloping. Ridge-and-valley terrain enhanced wind direction reversals, pressure-driven winds, as well as locally and regionally produced thermally-driven flow.