To explore the influence of interlocking depth and block number on the compressive performance of interlocking block masonry, seven kinds of interlocking depth and three kinds of block number are selected, and ABAQUS software is used to carry out numerical simulation analysis. The results show that when the interlocking depth is 10 mm, the compressive performance of masonry is better. With the increase in the number of blocks, the compressive strength of masonry decreases gradually. Based on the numerical simulation results, a recommended formula for the average compressive strength of interlocking block masonry is proposed.