Smart hydrogels comprising carboxymethyl guar gum and chitosan (CMGG/CS) have been fabricated using tetraethyl orthosilicate as the crosslinker. To render the hydrogels an improved biological efficacy, non-thermal plasma assisted surface modification have been performed using Ar, O2 and a mixture of Ar and O2 gases. Enhanced surface wettability was witnessed post-plasma treatment. AFM analyses revealed the topographical changes of the hydrogels at the nano-scale level without any adverse effect on their bulk physical structure. The hydrogels exhibited pH-responsive swelling with maximum swelling in neutral pH. The release of diclofenac sodium from the hydrogels confirmed their potential towards colon-targeted drug delivery. Excellent biofilm eradication features against E. coli was demonstrated by the hydrogels. Hemolytic assay on human RBCs affirmed their hemocompatibility. Moreover, the hydrogels were found to be remarkably biodegradable. Thus, non-thermal plasma assisted surface nano-textured CMGG/CS hydrogels can be efficaciously explored for their diverse applications in biomedicine.