Because of the limitation of body mass index (BMI) in distinguishing adipose mass from muscle, the tri-ponderal mass index (TMI) has been proposed as a new indicator for better assessing adiposity in children and adolescents. However, it remains unclear whether TMI performs better than BMI or other adiposity indices in predicting obesity status in childhood and obesity-related cardiovascular risk factors (CVRFs) in childhood or adulthood. We searched PubMed, Cochrane Library, and Web of Science for eligible publications until June 15, 2021. A total of 32 eligible studies were included in this systematic review. We found that TMI had a similar or better ability to predict body fat among children and adolescents than BMI. However, most of the included studies suggested that TMI was similar to BMI in identifying metabolic syndrome although TMI was suggested to be a useful tool when used in combination with other indicators (e.g., BMI and waist circumference). In addition, limited evidence showed that TMI did not perform better than BMI for identifying specific CVRFs, including insulin resistance, high blood pressure, dyslipidemia, and inflammation in children and adolescents, as well as CVRFs in adults. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero, CRD42021260356.