Purpose <p>Human existence is dependent upon the ability to get food for urgent metabolic demands. Hunger pains during periods of food insecurity may significantly diminish productivity and stability, and lead to depression and sleeplessness. This study is designed to suppress appetite using fluoxetine HCl and explore its repurposing prospective for emergency hunger suppression and weight management.</p> Methods <p>The study entails in silico reverse docking and molecular dynamics for ghrelin inhibition by targeting growth hormone secratagogue receptor (GHS-R1a). Using response surface methodology (RSM) and central composite design (CCD), fluoxetine HCl tablets having sustained release paradigm were formulated and evaluated. In vivo investigations were carried out on a chronic food restricted model and thereby validated.</p> Results <p>Fluoxetine with ghrelin receptor (PDB ID: 7F83) was found to be the most effective protein target. Molecular dynamics further demonstrated stable binding without major conformational changes after two independent simulations. No drug-polymer incompatibility was observed on FT-IR and DSC analysis. In vitro release study confirmed the prolonged release of drug up to 8&#xa0;h following Korsmeyer-Peppas model kinetics, with hardness values between 3.16 and 3.43&#xa0;kg/cm². The intermittent fasting rodent model showed pronounced corticosterone rise on food restriction that reduced significantly after treatment. Unlike ad libitum animals, food-restricted (FR) animals also had reduced locomotor activity owing to increased stress and anxiety. Finally, histological changes observed in the FR group validated this experimental model for investigating appetite regulation.</p> Conclusion <p>The research implies that fluoxetine could represent an excellent option for suppressing appetite during emergency with promising future prospects.</p> Graphical Abstract <p></p>