Selecting transshipment airports in various regions to achieve global express delivery and reduce cost is an essential issue for express delivery operators. This study provides a reference model for operators in their selection of regional transshipment airports with the objectives of minimizing costs of flight, cargo handling, and inventory. To verify the feasibility and application methods of the proposed model, this study conducts an empirical analysis of the operational data of FedEx in 2008. The results indicate that the Beijing Capital International Airport in China is the most cost-effective regional transshipment airport in the Asia-Pacific region. Finally, this study discusses the fluctuation of various airport costs in relation to the changing fuel prices via a sensitivity analysis, offering the operators a guide in selecting the optimal regional transshipment airports according to environment turbulence.