Abstract Context Clinical studies have found an association between yerba maté intake and beneficial physiological effects. Nevertheless, no systematic reviews have been conducted to shed light on the data supporting this association. Objective The present systematic review aimed to investigate the physiological effects of yerba maté. Data Sources Searches were performed in 6 databases (Embase, LILACS, Scopus, PubMed, SciELO, Web of Science) and 3 grey literature databases (OpenGrey, ProQuest, Google Scholar). Relevant publications were identified, and the reference lists of included studies were searched manually for randomized clinical trials, nonrandomized clinical trials, and observational studies investigating the physiological effects of yerba maté. Data Extraction Risk of bias was assessed using the Cochrane risk of bias tool for randomized trials and the Cochrane ROBINS-I (Risk Of Bias In Nonrandomized Studies of Interventions) tool. Joanna Briggs Institute critical appraisal tools were used for cross-sectional, case series, cohort, and case-control studies. The overall certainty of the evidence was estimated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) working group summary of findings table. Data Analysis Of 1096 studies identified, 32 were included. Studies showed consistent effects of yerba maté intake on metabolism improvement and antioxidant and anti-inflammatory activities in different populations. Benefits for body weight and composition, exercise performance, mood, and appetite, in addition cardio- and neuroprotective effects, were also observed. Risk of bias was categorized as high in 22 studies, moderate in 9 studies, and low in 1 study. The certainty of evidence ranged from moderate to very low. Conclusion The available literature indicates that yerba maté can be used within a balanced and healthy diet for prevention and adjuvant treatment of chronic diseases. Systematic Review Registration PROSPERO registration number CRD42020200196.