In this paper, an efficient multigrid-DEIM semi-reduced-order model is developed to accelerate the simulation of unsteady single-phase compressible flow in porous media. The cornerstone of the proposed model is that the full approximate storage multigrid method is used to accelerate the solution of flow equation in original full-order space, and the discrete empirical interpolation method (DEIM) is applied to speed up the solution of Peng–Robinson equation of state in reduced-order subspace. The multigrid-DEIM semi-reduced-order model combines the computation both in full-order space and in reduced-order subspace, which not only preserves good prediction accuracy of full-order model, but also gains dramatic computational acceleration by multigrid and DEIM. Numerical performances including accuracy and acceleration of the proposed model are carefully evaluated by comparing with that of the standard semi-implicit method. In addition, the selection of interpolation points for constructing the low-dimensional subspace for solving the Peng–Robinson equation of state is demonstrated and carried out in detail. Comparison results indicate that the multigrid-DEIM semi-reduced-order model can speed up the simulation substantially at the same time preserve good computational accuracy with negligible errors. The general acceleration is up to 50–60 times faster than that of standard semi-implicit method in two-dimensional simulations, but the average relative errors of numerical results between these two methods only have the order of magnitude 10−4–10−6%.