Background: Obesity is a multifactorial disorder linked to dysregulated energy balance and heightened cardiometabolic risk. Serotonin (5-hydroxytryptamine; 5-HT) is a pivotal regulator of appetite, lipid handling and thermogenesis, and imbalance be tween central and peripheral 5-HT pools favours weight gain. Neolamarckia cadamba, a Rubiaceae plant rich in indole alkaloids, is traditionally used for metabolic ailments, but its anti-obesity potential via serotonergic pathways is not well defined. Objective: To evaluate the effect of a standardized N. cadamba extract on central and peripheral 5-HT signalling and related metabolic outcomes in high-fat-diet (HFD) induced obese rats. Methods: Male Wistar rats were rendered obese by HFD feeding and then treated orally with graded doses of N. cadamba extract; lorcaserin served as a 5-HT2 C agonist reference. Body weight, food intake, adiposity index, oral glucose tolerance, in sulin sensitivity and serum lipid profile were recorded. Serotonin levels in hypothalamus and peripheral tissues were quantified, alongside expression of 5-HT2 C–POMC axis genes and TPH1-linked thermogenic markers. Liver and adipose tissues were examined histologically. Results: N. cadamba produced a dose-dependent reduction in body-weight gain and food intake, approaching the effect of lorcaserin. The extract improved dyslipidemia and glucose homeostasis and reduced visceral fat deposition. Mechanistically, treatment enhanced hypothalamic 5-HT activity and 5-HT2 C–POMC signalling, while suppressing peripheral 5-HT and TPH1 expression, a pattern consistent with enhanced satiety and activation of brown-adipose-tissue thermogenesis. Hepatic steatosis and adipocyte hypertrophy observed in HFD controls were markedly attenuated in extract-treated groups. Conclusion: These findings indicate that standardized N. cadamba exerts anti-obesity effects through dual serotonergic modu lation—stimulating central 5-HT2 C-mediated anorectic signalling while concomitantly dampening lipogenic peripheral 5-HT syn thesis. This dual-axis action, together with favourable metabolic and histological outcomes, supports N. cadamba as a promising plant-based candidate for safer obesity interventions. These preclinical data warrant isolation of active alkaloids and longer-term safety evaluation in models.