Fatty infiltration of muscle is increasingly recognized as a factor contributing to fall risk in middle-aged and older adults. The goal of this study is to systematically review the literature on the influence of fatty infiltration of muscle on falls and fall-related outcomes in middle-aged and older adults. Five databases - PubMed, the Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Web of Science, and Igaku Chuo Zasshi - were comprehensively searched. In addition, relevant studies were identified through hand searching of the reference lists of included articles. Study quality was assessed using the Newcastle-Ottawa scale. We initially identified 1,450 articles through database searches and an additional 26 articles through hand searching. After screening, 97 observational studies were included in the final analysis. Medical imaging modalities for fatty infiltration of muscle were CT, MRI, ultrasonography, and peripheral quantitative CT. Outcomes included falls, comfortable walking speed, maximum walking speed, the timed up and go test, the short physical performance battery, muscle strength, the 6-min walk test, the five times sit-to-stand test, the 30-s chair stand test, and other balance tests. Most of the surveyed studies indicated a potential association between lower extremity major fatty infiltration of muscle and falls. Similarly, fatty infiltration of muscle was associated with poorer fall-related outcomes. However, these studies included varied participant characteristics and methods for assessing fatty infiltration of muscle and exhibited a mixed risk of bias. In conclusion, our systematic review provides important evidence on assessing fatty infiltration of the muscle for fall prevention in older adults, while underscoring the need for careful interpretation and further research, considering variations in participant characteristics, assessment methods, and potential biases.