Obesity is a widespread health issue worldwide. Therefore, evaluating existing pharmaceuticals and developing new effective strategies to mitigate the problem is essential. Although literature reviews of a broad range of interventions for managing obesity exist, a recent evaluation of the efficacy of orlistat is lacking. This meta-analysis aims to quantify the efficacy of orlistat on body mass index (BMI) and the impact of age, dose, duration, and comorbidities. A literature search of orlistat on PubMed was carried out, and 177 placebo-controlled randomized clinical trials published in the last twenty years were identified. Sixteen studies that met the inclusion criteria were selected for further analysis. Two investigators independently extracted data from the clinical reports using a predefined protocol. We conducted a meta-analysis using random and mixed effects models with different moderators. We found that, on aggregate, the orlistat group reduced their BMI by 0.72 kg/m2 (P < 0.05) compared to the placebo group. In addition, a longer duration of intervention led to a greater decrease in BMI. Moreover, patients with comorbidities experienced a smaller change in BMI. In conclusion, the evidence suggests that orlistat moderately reduces BMI in obese subjects. The effect of lifestyle modifications, side effects, and drug interactions should be assessed in future studies.