This paper presents the results of an analysis focusing on large truck-involved work zone fatal crashes using seven-year crash data in the State of Florida. Decision tree/random forest models were applied to specifically detect critical crash patterns that result in a fatality outcome. Because of the imbalanced nature of crash severity data (very low frequency of fatal crashes compared with property damage only or injury), data were treated using random and systematic over-sampling techniques. Marginal effects were addressed using Shapley values to increase model explainability. From a methodological perspective, results showed that the combination of over-sampling techniques with ensemble random forests could significantly improve model performance in predicting fatal crashes (compared with conventional logistic regression models). Primary contributors included pedestrian involvement, lighting conditions, safety equipment, driver condition, driver age, and work zone locations. For pedestrian crashes, factors such as dark-not lighted conditions, distracted truck driver, and driver’s age (young drivers outside city limits, senior drivers inside city limits) were highly likely to be fatal. For non-pedestrian crashes, the combination of front airbag deployment with any restraint system other than shoulder and belt was quite likely to be fatal. Also, abnormal driver conditions increased the risk of a fatal outcome. Additionally, the presence of female drivers (as the second driver in multiple vehicle crashes) highly decreased crash severity, probably because females typically drive more carefully than males. Interestingly, truck driver actions and maneuvers as well as roadway design and other physical environment features (i.e., number of lanes, median type, roadway grade, and alignment) did not show significant contribution to the model.