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The purpose of this systematic review is to analyze the available evidence linking short-chain fatty acids (SCFA) to leptin's levels and production. We performed a systematic review using the PubMed/Medline database including primary articles written in English that measured leptin production or levels as well as SCFA used as an intervention, mechanism or outcome. The search yielded a total of 573 citations; 36 studies were included in the final analysis. The quality of the studies was analyzed through two validated tools based on objective criteria. Overall, the studies presented low risk of bias to construct and statistical validity. However, the majority presented a high risk of attrition and detection bias. In vitro studies (n = 8) consistently demonstrated that SCFA stimulate leptin expression in adipocytes through activation of free fatty acid receptor 3 (FFAR3). In animal studies (n = 24), interventions to modulate high-fat diet outcomes predominantly caused a decrease in circulating leptin levels and increased SCFA, associated with suppressed weight gain. Control of dysbiosis through administration of prebiotics and probiotics also played a role in leptin synthesis in animal studies. In human studies (n = 4) leptin was mainly correlated with adiposity but dysbiosis interfered with this relationship. We conclude that the association between SCFA and leptin remains incompletely understood but occurs mainly through the activation of FFAR3 in adipocytes. However, body fat rather than SCFA remains the main driver for leptin synthesis in vivo. Future studies should aim to better clarify the role of SCFA in regulating leptin production in vivo. [ABSTRACT FROM AUTHOR]