Hypothalamus is central to food intake and satiety. Recent data unveiled the expression of N-methyl-D-aspartate receptors (NMDAR) on hypothalamic neurons and their interaction with GABAA and serotoninergic neuronal circuits. However, the precise mechanisms governing energy homeostasis remain elusive. Notably, in females, the consumption of progesterone-containing preparations, such as hormonal replacement therapy and birth control pills, has been associated with hyperphagia and obesity-effects mediated through the hypothalamus. To elucidate this phenomenon, we employed the progesterone-induced obesity model in female Swiss albino mice. Four NMDAR modulators were selected viz. dextromethorphan (Dxt), minocycline, d-aspartate, and cycloserine. Obesity was induced in female mice by progesterone administration for 4 weeks. Mice were allocated into 7 groups, group-1 as vehicle control (arachis oil), group-2 (progesterone + arachis oil), and group-3 as positive-control (progesterone + sibutramine); other groups were treated with test drugs + progesterone. Various parameters were recorded like food intake, thermogenesis, serum lipids, insulin, AST and ALT levels, organ-to-body weight ratio, total body fat, adiposity index, brain serotonin levels, histology of liver, kidney, and sizing of fat cells. Dxt-treated group has shown a significant downturn in body weight (p