Background The importance of leptin in controlling body mass has recently gained more attention. Its levels are directly associated with the amount of fat mass, but not necessarily dependent on it. Exercise has great potential in reducing leptin levels, however the response of exercise to this cytokine is still not well understood. Objective The objective of the review was to analyze the effects of physical exercise on plasma leptin concentration, either acutely (post-exercise/training session) and/or after a training period (short- or long-term), as well as to investigate the existence of possible moderating variables. Methods The studies included in this systematic review were published between 2005 and May 2023. Only peer-reviewed studies, available in English, performed with humans that evaluated the effects of any form of exercise on leptin levels were included. The search was conducted on May 03, 2023, in Embase (Elsevier), MEDLINE via PubMed®, and Web of Science (Core collection). The risk of bias in the included trials was assessed by the Physiotherapy Evidence Database tool, considering 11 questions regarding the methodology of each study with 10 questions being scored. The data (n, mean, and standard deviation) were extracted from included studies to perform random effects meta-analyses using standardized mean difference between the pre- and post-intervention effects. Results Twenty-five studies (acute effect: 262 subjects; short- and long-term effect: 377 subjects) were included in this systematic review and meta-analysis. Short- and long-term physical exercise and caloric restriction plus exercise reduce plasma leptin levels, presenting statistically significant differences (p<0.001); as well as acute effect (p = 0.035), however the latter result was influenced by the pre-exercise meal as shown in the subgroup analysis. In this meta-analysis the effect of moderating factors on leptin reduction, not addressed by past reviews, is verified, such as the relationship with caloric restriction, exercise intensity and pre-exercise meal on acute responses. Conclusion Both acute and chronic exercise reduce leptin levels, yet the acute effect is dependent on the pre-exercise meal. In addition to having a long-term reduction in leptin levels, the minimum amount of weekly exercise to have a significant reduction in plasma leptin is 180 minutes of moderate-intensity exercise and 120 minutes of high-intensity exercise.