Road departure (RD) crashes are among the most severe crashes that can result in fatal or serious injuries, especially when involving large trucks. Most previous studies neglected to incorporate both roadside and median hazards into large-truck RD crash severity analysis. The objective of this study was to identify the significant factors affecting driver injury severity in single-vehicle RD crashes involving large trucks. A random-parameters ordered probit (RPOP) model was developed using extensive crash data collected on roadways in the state of Kentucky between 2015 and 2019. The RPOP model results showed that the effect of local roadways, the natural logarithm of annual average daily traffic (AADT), the presence of median concrete barriers, cable barrier-involved collisions, and dry surfaces were found to be random across the crash observations. The results also showed that older drivers, ejected drivers, and drivers trapped in their truck were more likely to sustain severe single-vehicle RD crashes. Other variables increasing the probability of driver injury severity have included rural areas, dry road surfaces, higher speed limits, single-unit truck types, principal arterials, overturning-consequences, truck fire occurrence, segments with median concrete barriers, and roadside fixed object strikes. On the other hand, wearing seatbelt, local roads and minor collectors, higher AADT, and hitting median cable barriers were associated with lower injury severities. Potential safety countermeasures from the study findings include installing median cable barriers and flattening steep roadside embankments along those roadway stretches with high history of RD large-truck-related crashes.