Programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis and tumor-associated macrophages (TAMs) in the tumor microenvironment are closely related to carcinogenesis. TAMs are mainly categorized as the anti-tumoral M1 phenotype and the pro-tumoral M2 phenotype, with M2-TAMs being the main type of infiltrating macrophages in tumor tissue. Recent research has mainly focused on the inhibition of the anti-tumor effect of TAMs by the PD-1/PD-L1 axis, and the involvement of the cytokines, chemokines, and exosomes that are secreted by TAMs in regulating the expression of PD-1/PD-L1. Here, the authors review the role of PD-1/PD-L1 and TAMs in tumorigenesis, summarize the possible interactions between the them, and discuss the impact of targeted regulation of TAMs on the effectiveness of PD-1/PD-L1 monoclonal antibody therapy for tumors.