This Meta-analysis aimed to clarify the microbial distribution of periprosthetic joint infection (PJI) and to explore therapeutic strategies for specific pathogens associated with PJI. PubMed, CNKI (China National Knowledge Infrastructure), and Wanfang databases were searched for relevant literature up to November 8, 2022. Studies reporting on the distribution of PJI pathogens and their antimicrobial susceptibility were included. Data on pathogen distribution and antibiotic resistance profiles were collected. Studies meeting the criteria underwent quality assessment used the Joanna Briggs Institute (JBI) critical appraisal tool for analytical cross-sectional studies. Meta-analysis was conducted using STATA 17 software. A total of 25 studies were included, consisting of 22 retrospective studies and 3 randomized controlled trials. Among these 25 studies, the overall prevalence of Gram-positive bacteria was 76% (95% CI is [0.72, 0.80], P<0.01), Gram-negative bacteria was 18% (95% CI is [0.15, 0.21], P<0.01), fungi was 3% (95% CI is [0.02, 0.04], P<0.01), and mycobacteria was 2% (95% CI is [0.01, 0.03], P<0.01). Coagulase-negative Staphylococci and Staphylococcus aureus are the two main pathogens contributing to periprosthetic joint infections. Clinical practice should optimize more effective utilization of existing drugs, mitigate the development of bacterial resistance, and seek new drug targets to expand the range of antibiotic options for periprosthetic joint infections.