Background Reduced physical function and polypharmacy (PPha) are two highly prevalent negative effects of aging, which are expected to increase more, since demographic aging is expected to grow rapidly within the next decades. Previous research suggests that polypharmacy (PPha) is a predictor of poor physical function and vice versa in older adults and therefore we conducted a systematic review of the literature to summarize and critically analyze the relationship between physical function and PPha and vice versa in older adults, in order to provide recent scientific evidence. Methods We searched MEDLINE and Embase from their inception to 19th October 2018 for English-language observational studies or trials assessing the effect of PPha on physical function and vice versa in older adults. Two investigators independently extracted study data and assessed the quality of the studies, after having screened the available studies from the literature search. Any disagreement was resolved by consensus. Results Eighteen observational studies met the inclusion criteria. Eight studies assessed the impact of physical function on PPha and ten studies assessed the impact of PPha on physical function. Regarding the studies with PPha measurements as the outcome, all of them, except for one, found that better physical function is associated with lower risk of PPha. Likewise, all the studies with physical function measurements as the outcome, except for one, suggested that PPha is associated with lower physical function. Discussion Evidence examining the effect of PPha on physical function and vice versa in older adults suggests a strong bidirectional association between these two factors and clinicians should be aware of this strong relationship. The limitations of our study include the high variability in PPha definitions and physical function measures, and the treatment of PPha and physical function as constant instead of time-varying variables in the studies' analyses.