Monosodium glutamate (MSG) has been implicated in female reproductive toxicity through endocrine disruption, oxidative stress, inflammation, and apoptosis. This study investigated the protective role of Sorghum bicolor extract (SBE), a polyphenol-rich nutraceutical, against MSG-induced reproductive dysfunction in female Wistar rats, integrating in vivo outcomes with in silico docking analysis. Rats were exposed to MSG (4 g/kg) with or without SBE supplementation (100 mg/kg) orally for 28 days. Estrous cycle, sexual behaviors, hormonal profiles, oxidative and nitrosative stress markers, inflammatory mediators, and apoptotic regulators were assessed. Molecular docking evaluated the interactions of SBE phytochemicals with LHB and LHCGR. MSG disrupted the pituitary-gonadal axis, shortened estrous phases, suppressed reproductive behaviors, increased lipid peroxidation, activated NF-κB, and triggered mitochondrial apoptosis. SBE restored gonadotropins and steroid hormones, normalized estrous cycle, enhanced antioxidant defenses, suppressed inflammation, and prevented apoptosis. Docking analysis revealed strong ligand-protein interactions, supporting endocrine and cellular protection. Conclusively, SBE confers robust gonadoprotective effects against MSG toxicity through endocrine restoration, antioxidant, anti-inflammatory, and anti-apoptotic mechanisms validated in vivo and in silico.