Neem (Azadirachta indica) exhibits multiple therapeutic benefits in preclinical studies, but clinical studies are lacking. This clinical study investigated the efficacy and safety of an aqueous A. indica leaf and twig extract (NEEM) on metabolic parameters in subjects with metabolic syndrome (MetS). Subjects were randomized to receive (1) placebo or (2) 125 mg, (3) 250 mg, or (4) 500 mg of NEEM twice daily (n = 20/group) for 12 weeks. Fasting blood sugar (FBS) and insulin, postprandial blood sugar (PPBS), insulin resistance (IR), hemoglobin A1c (HbA1c), endothelial function, circulating markers of inflammation and oxidative stress, lipid profiles, and platelet aggregation were measured at weeks 0, 4, 8, and 12. NEEM supplementation dose dependently improved the trajectories for FBS, PPBS, IR, and HbA1c over time, as well as endothelial function and most markers of inflammation and oxidative stress. Therefore, NEEM may be considered a promising therapeutic to attenuate the hyperglycemia and associated cardiometabolic derangements in people with MetS. Clinical trial registration no.: CTRI/2019/03/018034 [registered on: March 12, 2019].