Potent incretin-based therapy shows promise for the treatment of obesity along with reduced incidence of cardiovascular events in patients with preexisting cardiovascular disease and obesity. This study assessed the efficacy and safety of the incretin-based obesity treatments, once-weekly subcutaneous semaglutide 2.4 mg and tirzepatide 10 or 15 mg, in people with obesity without diabetes. Of the 744 records identified, seven randomized controlled trials (n = 5140) were included. Five studies (n = 3288) investigated semaglutide and two studies (n = 1852) investigated tirzepatide. The treatment effect, shown as placebo-subtracted difference, on body weight was −15.0% (95% CI, −17.8 to −12.2) with −12.9% (95% CI, −14.7 to −11.1) for semaglutide and −19.2% (95% CI, −22.2 to −16.2) for tirzepatide. The treatment effect on waist circumference was −11.4 cm (95% CI, −13.7 to −9.2) with −9.7 cm (95% CI, −10.8 to −8.5) for semaglutide and −14.6 cm (95% CI, −15.8 to −13.4) for tirzepatide. The adverse events related to semaglutide and tirzepatide were primarily of mild-to-moderate severity and mostly gastrointestinal, which was more frequent during the dose-titration period and leveled off during the treatment period. This emphasizes that once-weekly subcutaneous semaglutide 2.4 mg and tirzepatide 10 or 15 mg induce large reductions in body weight and waist circumference and are generally well-tolerated.