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Permeability of porous media in subsurface environments is subject to potentially large uncertainties due to the heterogeneity of natural systems. In this study, a first-order reliability method (FORM) is combined with a lattice Boltzmann method (LBM) to estimate the permeability of randomly generated porous media. The proposed procedure provides an increased ease of addressing complex pore structures by employing LBM to model fluid flow, while inheriting the computational efficiency from FORM. Macroscale- equivalent permeability can thus be estimated with significantly reduced computational efforts, while maintaining a connection to the complex microscale fluid dynamics within a pore structure environment. Implemented on several randomly generated porous media domains, the proposed method provides 13–120 times the efficiency compared to Monte Carlo methods.