Hydrogels are three-dimensional colloidal dispersions composed of a complex network of hydrophilic polymers meant for the controlled and site-specific delivery of a variety of drugs. Hydrogels based upon the combination of synthetic polymers and Xanthan gum not only increase the swelleability, drug loading capacity but also provide a promising platform for the controlled delivery of both hydrophilic and hydrophobic drugs. In the present study, pH-responsive hydrogels based upon Xanthan gum (XG)/Eudragit-S100 (Eu-S100) were prepared for the duodenal delivery of an anti-diabetic drug Metformin HCl (MT) at a controlled rate. Formulations were characterized for swelleability, drug release, surface morphology and compatibility with the loaded drug. The results of the study showed that all the formulations provided pH-dependent swelleability and drug release but the formulation based upon the combination of natural and synthetic polymer provided steady-state drug release at duodenal pH with very less amount of drug release at stomach pH. The release mechanism in that formation was the combination of diffusion/erosion. The FTIR analysis revealed no gel-drug interaction and Scanning electron microscopy (SEM) revealed the porous structure in a gel matrix with interconnected tunnels to facilitate the diffusion of water and drug molecules. Taken together, the findings of the present study supported the assumption that a combination of natural gum and a synthetic polymer may provide a very useful pH-responsive extended- release drug delivery system for hydrophilic and lipophilic drugs whose basic site of absorption is the small intestine. Prospective researchers are suggested to conduct toxicity and pharmacokinetic studies on in vivo models