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Background: Staphylococcus aureus ( S. aureus ) infecting animals and humans via close contact, handling, or consuming contaminated products is a growing public health concern. In Ethiopia, it is important to examine the overall prevalence of S. aureus , patterns of multidrug resistance, and potential risks in human-animal interface settings. Thus, this review was conducted to estimate the pooled prevalence of S. aureus , its multidrug resistance, and potential risk factors for worker-animal-working equipment interactions., Methods: This systematic review and meta-analysis were carried out by the PRISMA guidelines. The research articles were searched from PubMed, HINARI, Web of Sciences, and Google Scholar databases., Results: This meta-analysis included 13 independent articles and 52 dependent studies. In total, 5,329 humans, 5,475 animals, and 5,119 samples of working equipment were analyzed. The pooled prevalence of S. aureus at the interfaces between humans, animals, and working equipment was 22%, there was a high level of heterogeneity (I 2  = 94%: p  < 0.01). The overall pooled prevalence of S. aureus in dairy farm sources was 23% (95% CI, 17-30%) compared to 18% in abattoirs. The pooled prevalence of S. aureus was estimated to be 25% for human sources, 23% for animal sources, and 19% for working equipment. The total multidrug resistance (MDR) rate was 27%. The present study illustrates that a predominant antimicrobials comprising ampicillin, penicillin, chloramphenicol, tetracycline, and ciprofloxacin, accounts for the development of resistance in S. aureus strains, with a prevalence of 72%. According to the qualitative assessment of potential risk factors, animal age, worker education, lactation stage, and hand washing by milkers influenced the circulation of S. aureus at animal-worker and working equipment interfaces., Conclusion: The pooled prevalence of S. aureus at the interface of human,-and animal-working equipment was quantified at 22%. S. aureus was found in humans, animals, and equipment at nearly the same rate. The results of this study demonstrate that S. aureus is hazardous and circulates among animals, workers, and equipment: farmers, animal owners, employees, and the public need to be educated about S. aureus . Moreover, animals and work equipment should be included in the control and prevention of S. aureus infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mengistu, Getnet, Mebratu and Fenta.)