As information and communication technology evolves and expands, business and markets are linked to form a complex international network, thus generating plenty of cross-border trading activities in the supply chain network. Through the observations from a typical cross-border supply chain network, this paper introduces the fuzzy reliability-oriented 2-hub center problem with cluster-based policy, which is a special case of the well-studied hub location problem (HLP). This problem differs from the classical HLP in the sense that (i) the hub-and-spoke (H&S) network is grouped into two clusters in advance based on their cross-border geographic features, and (ii) a fuzzy reliability optimization approach based on the possibility measure is developed. The proposed problem is first modeled through a mixed-integer nonlinear programming (MINLP) formulation that maximizes the reliability of the entire cross-border supply chain network. Then, some linearization techniques are implemented to derive a linear model, which can be efficiently solved by exact algorithms run by CPLEX for only small instances. To counteract the difficulty for solving the proposed problem in realistic-sized instances, a tabu search (TS) algorithm with two types of move operators (called “Swap I” and “Swap II”) is further developed. Finally, a series of numerical experiments based on the Turkish network and randomly generated large-scale datasets are set up to verify the applicability of the proposed model as well as the superiority of the TS algorithm compared to the CPLEX.