Identifying novel compounds with therapeutic potential is a main area of interest in biomedical research. Tetrahydroindenoindole (THII) has emerged as a compound of interest due to both its antioxidant properties and its action as a pharmacological activator of the enzyme cytochrome b5 reductase 3. However, there is a lack of comprehensive synthesis of findings, particularly concerning the effects of THII on metabolism in mice under non-disease conditions. This systematic review with meta-analysis aims to bridge this gap by analyzing existing studies. Our findings demonstrated that THII supplementation reduced body weight gain, while fat mass remained unchanged. Fasting blood glucose and plasma insulin levels, as well as insulin levels during the glucose tolerance test, showed no changes. However, glucose tolerance improved with THII supplementation during the glucose tolerance test, particularly in animals under a high-fat diet. THII supplementation also increased O2 consumption and CO2 production, with a tendency to lower respiratory quotient. In mitochondria, THII supplementation did not affect state 3 respiration, while increased state 4, and decreased the respiratory exchange ratio. Notably, mitochondrial H2O2 production during state 4 respiration and ATP levels also remained unchanged. Furthermore, THII supplementation reduced NADPH-dependent O2 uptake, NADPH-dependent H2O2 production, and lipid peroxidation. Despite the limitations and potential sources of bias identified, we observed valuable outcomes linked to THII supplementation. The significant impact on energy metabolism, mitochondrial function, and oxidative stress underscores THII as a promising intervention with translational relevance for aging-related alterations, enhancing healthspan, and targeting metabolic-associated diseases such as obesity or diabetes.