Obesity and overweight represent pressing global health concerns, with their mitigation posing a formidable challenge. Among the numerous strategies employed to tackle these conditions, the effectiveness of pharmacological interventions like Semaglutide and Tirzepatide has garnered significant attention. This research aims to provide a thorough examination of the efficacy, safety, and tolerability of Tirzepatide and Semaglutide in promoting weight loss among obese patients. This study meticulously reviewed all relevant experiments involving anti-obesity medications across multiple reputable databases. Sensitivity analyses were conducted using various robust techniques such as the Bucher method, applying different estimands and time points to ensure the accuracy and reliability of the findings. The results revealed that subcutaneous administration of Tirzepatide and Semaglutide led to significant reductions in BMI, body weight, and waist circumference compared to control groups. Notably, the 15 mg dose of Tirzepatide achieved the most substantial weight loss. While Tirzepatide and Semaglutide are not yet directly comparable in their entirety for weight management, this study utilized a matching-adjusted indirect treatment comparison approach to evaluate their effectiveness. The findings indicate that Tirzepatide demonstrates superior efficacy in weight reduction compared to Semaglutide, highlighting its potential as a more effective pharmacological option for managing chronic obesity.