Intricacy of the supply chains for deteriorating products, involving multiple retailers with unequal lot sizes and multiple deliveries is simplified in this article by optimizing the replenishment cycle, investment in preservation technology, and number of deliveries. This study proposes a multi-tier supply chain model consisting of a single manufacturer and multiple retailers. A single-setup multiple deliveries (SSMD) policy is adopted considering the synchronized cycle time of manufacturers with that of retailers and the delivery of unequal lot size for each retailer. Preservation technology is used at retailers to minimize the effects of deterioration in a way that the magnitude of decrease in deterioration reduces for additional investment in preservation technology. A centralized supply chain model is proposed by defining a nonlinear mathematical model for maximizing total profit through an analytical optimization technique and an algorithm. Numerical experiments are exhibited to validate the applications of the provided model. The results exhibit that the proposed preservation policy increases the product’s lifetime and the total profit by reducing the number of shipments/transportation and increasing the lot size. The SSMD policy helps to reduce the preservation cost and increase the total profit. Some managerial insights are provided for the decision makers for applying the proposed model.