Safety and efficiency are two critical issues at highway-rail grade crossings (HRGCs) and their nearby intersections. The standard preemption provides little or no consideration to pedestrian safety, or traffic signal efficiency of signalized intersections near highway-rail grade crossings. To solve these issues, a case study was conducted, and developed a simulation-based optimization methodology for estimating traffic signal timing plans on arterial corridors with multiple intersections near HRGCs. Genetic algorithm (GA) was used as the optimization approach, and a new transition preemption strategy for dual tracks (TPS_DT) and a train arrival prediction model were integrated in the proposed methodology. A sensitivity analysis with different train traffic scenarios was conducted. Measurements of effectiveness (MOEs) used for evaluation include rate of pedestrian cutoffs, intersection vehicle delay, and corridor vehicle delay. It was concluded that the methodology can significantly improve both the safety and efficiency of traffic corridors with multiple intersections near HRGCs.