Objective To compare the efficacy and safety of different cyclin-dependent kinase4/6 inhibitor (CDK4/6i) combined with endocrine therapy (ET) for HR+/HER2- advanced or metastatic breast cancer based on mesh meta-analysis. Methods Randomized controlled trials (RCTs) of CDK4/6i in the treatment of HR+/HER2- metastatic/advanced breast cancer were searched in PubMed, EMbase, Web of Science, The Cochrane Library, CNKI, Wanfang, VIP, and SinoMed databases from inception to August 2023. Bayesian network meta-analysis was performed by R 4.2.0 software. Results Finally, 18 RCTs in 25 articles, covering 8 031 patients, involving 11 treatment regimens were included. There were no statistical differences in progression-free survival (PFS) or overall survival (OS) between CDK4/6i+ET combinations. DAL+FUL ranked first in PFS rate, and RIB+FUL ranked first in OS rate. In terms of effectiveness, ABE+AI and ABE+FUL ranked first in objective response rate (ORR) and clinical benefit rate (CBR), respectively. In terms of safety, there were significant differences in grade 3-4 AEs and SAE among some CDK4/6i types (P<0.05). Conclusion Current evidence shows that CDK4/6i+ET is superior to ET alone in the treatment of HR+/HER2- advanced/metastatic breast cancer, and different combinations of CDK4/6i+ET have the same or similar effects, but the combination has a higher incidence of adverse reactions, and a reasonable treatment plan should be selected according to the individual situation of patients.