The truck platoon is one of the most promising connected and autonomous vehicle (CAV) technologies that can reduce fuel consumption and emission, enhance traffic safety, and increase roadway capacity. It is predicted to become mainstream in the next decade. Therefore, it is imperative to fully investigate the safety issues of the truck platoon before its large-scale deployment. However, studies on the lateral safety of the truck platoon under extreme weather, especially crosswinds are still lacking. To fill such a research gap, the current study contributes to the literature by proposing a reliability-based framework to evaluate the safety of the truck platoon regarding incursion into neighboring lanes due to extreme weather, especially crosswinds. The proposed approach involved three main steps: (1) the computational fluid dynamics (CFD) simulation of the aerodynamics of the truck platoon; (2) the truck platoon driving simulation under crosswind; and (3) the advanced response surface model development and the reliability analysis. Four main factors regarding lateral safety of the platoon were considered: wind speed, road friction coefficients, driving speed, and inter-vehicle spacing. The maximum lateral displacement (MLD) was chosen as a measure of lateral safety. The results showed that there was a significant difference between the aerodynamics of a single truck and that of the truck platoon vehicles and the inter-vehicle spacing between trucks within the truck platoon barely influenced the MLD. The MLD was largest for the leading truck as compared to those of the following trucks. The inter-vehicle spacing didn’t have a significant influence on MLD when the inter-vehicle spacing is shorter than 1.5 times of the truck length, while the other factors impacted the MLD significantly. In addition, the support vector regression with the radial basis function outperformed the other response surface functions. Based on reliability analysis, the risk level of the truck platoon was quantified using the safety index, and the impact of contributing factors towards the safety index of the truck platoon was also evaluated. This study confirmed that the proposed framework could be applied to evaluate the lateral safety of the truck platoon. The findings provide important practical implications for the decision-making of transportation management agencies and tailored countermeasures in the CAV) environment.