BackgroundMachine learning is a promising and powerful technology with increasing use in orthopedics. Periprosthetic joint infection following total knee arthroplasty results in increased morbidity and mortality. This systematic review investigated the use of machine learning in preventing periprosthetic joint infection.MethodsA systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed was searched in November 2022. All studies that investigated the clinical applications of machine learning in the prevention of periprosthetic joint infection following total knee arthroplasty were included. Non-English studies, studies with no full text available, studies focusing on non-clinical applications of machine learning, reviews and meta-analyses were excluded. For each included study, its characteristics, machine learning applications, algorithms, statistical performances, strengths and limitations were summarized. Limitations of the current machine learning applications and the studies, including their ‘black box’ nature, overfitting, the requirement of a large dataset, the lack of external validation, and their retrospective nature were identified.ResultsEleven studies were included in the final analysis. Machine learning applications in the prevention of periprosthetic joint infection were divided into four categories: prediction, diagnosis, antibiotic application and prognosis.ConclusionMachine learning may be a favorable alternative to manual methods in the prevention of periprosthetic joint infection following total knee arthroplasty. It aids in preoperative health optimization, preoperative surgical planning, the early diagnosis of infection, the early application of suitable antibiotics, and the prediction of clinical outcomes. Future research is warranted to resolve the current limitations and bring machine learning into clinical settings.