The objective of this research was to investigate the impact of roadway geometrics and speed on lateral stability of tractor-semitrailer on combined alignments of freeways since the current design guidelines of combined alignments are not available in China. A closed-loop vehicle dynamic simulation model was established using TruckSim multibody dynamics software. The maximum wheel side friction demand and lateral load transfer ratio were used to measure the skidding and rollover risks, and the variation laws of each indicator were determined by developing the controlled variable simulation scenarios. Based on the theory of statistical analysis, an orthogonal test was designed, and the effects of various impact factors on the lateral stability of the tractor-semitrailer were analyzed. The models for lateral stability indicators were developed by multiple linear regression analysis and applied to evaluate the driving risk of tractor-semitrailer on a wet road surface. The results showed that the radius and speed have significant effects on the lateral stability while the effect of the downgrade is of general significance. In addition, lower safe speed should be adopted on wet road surfaces of curved downgrade. This paper proposed a surrogate approach to road safety analysis and the models can be used for building the freeway driving security system.