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In this paper, the mechanical performance improvement of traditional penetration mortise–tenon (PMT) connections reinforced by self-tapping screws (STSs) were experimental and numerical studied. Four unreinforced penetration mortise–tenon connections and four STS-reinforced connections were experimentally investigated under monotonic and low-frequency cyclic loading. Besides, the numerical model of PMT connections reinforced by STSs with different diameters and yield strength were established and analyzed.Their failure modes, rotational stiffness, moment-resisting capacity, ductility, and seismic behavior were studied. The experimental results indicated that the STSs reinforcements could enhance the moment-resisting capacity of the penetration mortise–tenon connection. Compared with unreinforced connections, the initial stiffness of STS-reinforced connections increased by 75% with the moment-resisting capacity increasing by 69%, respectively. Furthermore, the STSs reinforcement method can effectively restrict the pull-out of tenon during the whole loading process. Numerical simulation results showed that the yield strength of STS has little effect on the moment-bearing behavior of the connection. The diameter of STS significantly influences the connection performance, and the diameter of 8 mm is suggested.