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This chapter proposes a hybrid heuristic method combining a clustering search (CS) metaheuristic with an exact algorithm to solve a two-stage capacitated facility location problem (TSCFLP). The TSCFLP consists of defining the optimal locations of plants and depots and the product flow from plants to depots (first stage) and from depots to customers (second stage). The problem deals commonly with cargo transportation in which products must be transported from a set of plants to meet customers’ demands passing out by intermediate depots. The main decisions to be made are related to define which plants and depots must be opened from a given set of potential locations, which customer to assign to each one of the opened depots, and the amount of product flow from the plants to the depots and from the depots to the customers. The objective is to minimize costs satisfying demand and capacity constraints. Computational results demonstrate that our method was able to find good solutions when comparing it directly with a commercial solver and a genetic algorithm (GA) reported in a recent chapter found in the literature, requiring less than 1.5% and 41% of the computational time performed by these methods, respectively. Thus, our hybrid method combining CS with an exact algorithm can be considered as a new matheuristic to solve the TSCFLP.