Drivers with different levels of familiarity with a roadway may respond dissimilarly to traffic and environmental conditions, which can, in turn, influence the severity of crash outcomes. Route familiarity constitutes an important human-related factor, as it may shape risk perception, situational awareness, and vehicle control, particularly in single-vehicle crashes occurring outside urban areas. Accordingly, analyzing crash injury severity without accounting for drivers’ familiarity with the route may obscure meaningful behavioral and contextual differences. In this study, a database of extra-urban single-vehicle crashes was utilized to investigate injury severity separately for familiar and unfamiliar drivers. To this end, independent logistic regression models were estimated for each group, allowing the effects of roadway characteristics, environmental conditions, temporal factors, and driver- and vehicle-related attributes to be examined in a disaggregated manner. The results indicate that certain factors, including the presence of a median barrier, crash type, and time of crash occurrence, are consistently associated with injury severity across both driver groups. In contrast, variables such as nighttime lighting conditions, driver gender, vehicle type, and driver age exhibit group-specific effects, suggesting heterogeneous mechanisms through which crash severity is shaped for familiar versus unfamiliar drivers. These findings imply that treating drivers as a homogeneous population may lead to oversimplified interpretations of crash severity determinants. Overall, the study highlights the analytical value of distinguishing drivers based on route familiarity when modelling single-vehicle crash severity and underscores the need for safety interventions that are tailored to the distinct risk profiles of drivers operating in familiar and unfamiliar road environments.