The preservation of perishable food items within the cold chain is a critical aspect of modern food logistics. Traditional refrigeration systems consume large amounts of energy, without an optimal temperature distribution, leading to potential food spoilage and economic losses. In recent years, the integration of Phase Change Materials (PCMs) into cold chain systems has emerged as a promising solution to address these challenges. This article presents a comprehensive analysis of the utilization of PCMs for food preservation in a refrigerated truck, focusing on the impact on temperature control, phase change fraction, costs, and energy savings. The effectiveness of PCM-based refrigeration system to maintain the refrigerated truck at a temperature of −18 °C under various scenarios and environmental conditions using a transient model was evaluated. The TRNSYS model includes a representation of a conventional refrigerated van’s system, with simulations conducted in a Mediterranean climate (Naples). The model’s core components consist of Type 56 for cooling load estimation and Type 1270a for the new PCM component. Results indicate that for guaranteeing −18 °C for 10 h, 96.4 kg and 102.2 kg of E-26 and E-29 PCM are needed, respectively, for scenarios with 10 door openings during transportation and for two different velocities of the truck: 30 and 80 km h−1. Results indicate that the incorporation of PCMs in the refrigerated van leads to significant improvements in temperature stability and uniformity, thereby extending the shelf life of perishable food products and reducing the risk of spoilage. Furthermore, the analysis shows that, using the PCMs, a significant reduction of the energy costs can be obtained (up to a maximum of around 79%).