Background: Obesity or overfat (i.e., excessive fat accumulation in the host) contributes to cerebrocardiovascular and other diseases. Orlistat is a good obesity medication, unlike other drugs that have higher cardiac toxicity. It reversibly inhibits pancreatic and gastric lipases, and improves oxysterol metabolism. This study summarizes and elaborates the impact of orlistat on BMI in overweight and obese adult patients. Methods: All authors systematically searched and retrieved 288 controlled trial articles on orlistat and BMI from three databases, two registries, and citation searches using specific keywords. The quality and bias risks were determined by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), Risk of Bias in Non-Randomized Study (ROBINS-I), and modified Jadad scale. R version 4.2.2 software calculated the effect size and the analysis of covariance (ANCOVA) effect, and subsequently analyzed using metafor. Results: This novel meta-analysis included 114 studies with 24,600 overweight or obese participants. We showed that orlistat substantially reduced BMI (mean difference −0.78 [−0.94, −0.63], p < 0.0001; I2 = 90.19%, pheterogeneity < 0.0001). Similarly, meta-regression showed a significant impact of orlistat daily dose (ß = −0.0019), yet not for duration (ß = −0.0024) and location (ß = −0.8591, −0.0190). Conclusion: Orlistat has the capacity to reduce BMI in overweight and obese individuals. Medical practitioners shall prescribe orlistat as a BMI lowering agent to complement other intervention in those patients