Background: Sustained release gastro retentive drug delivery systems enable prolonged and continuous input of the drug to the gastrointestinal tract and improve the bioavailability of medications that are characterized by the narrow therapeutic window. Aim: The objective of this study encompasses the application of the response surface approach in the development of pharmaceutically active hydrodynamically balanced system (HBS)-containing metronidazole (MN). Materials and Methods: Experiments were performed according to a 32 factorial design to evaluate the effects of gel forming polymers, low molecular weight chitosan, and medium molecular weight chitosan on the buoyancy and time taken for 60% drug release (t60%). The effect of the two independent variables on the response variables was studied by surface response curves and contour plots generated by the Minitab-17 software. Results: The drug-excipients interaction studies performed by differential scanning calorimetry revealed drug polymer compatibility, and hence, formulations were prepared by physical blending of MN and polymers by encapsulation into hard gelatin capsules. In vitro buoyancy study and drug release study in the gastric environment showed the efficacy of the HBS to remain gastro retentive (buoyant) for a longer period and simultaneously sustained the release of the drug. Conclusion: Thus, a conclusion might be brought forward that the present HBS could be an ideal system for stomach specific sustained delivery of MN and would be useful to patients where the prolonged therapeutic action on the infection site caused by microorganisms is required.