The incidence of oro-dental disorders has emerged as a serious threat to the healthcare sector owing to the increasing complexity of the oral microbiome. Significant advances in biomaterial research have led to the advent of a plethora of drug delivery systems including nanocarriers, dendrimers, hydrogels and other kinds of stimuli-responsive polymeric biomaterials. Anti-microbial peptides (AMPs) have engendered considerable interest in the past decades as potential alternatives to traditional disinfecting agents and also emerged as potent antibiofilm agents. Among the most viable approaches in targeted drug delivery, hydrogels incorporated with AMPs are emerging as bio-functional platforms yielding increased stability and bioavailability. The antibacterial and antibiofilm activities of Nisin are studied using microbiological methods followed by the synthesis of Nisin loaded PVA-Alginate hydrogel for dental treatment. The physicochemical characteristics of Nisin loaded hydrogel were done by swelling behavior, release kinetics assay, FTIR spectroscopic methods and cytotoxicity studies. Nisin showed antibacterial activity towards clinical isolates of drug-resistant bacteria and the antibiofilm and anti-adhesion studies demonstrated that Nisin could control the bacterial count in the test sample. The polymerization of Nisin into hydrogels was done and the physico-chemical characterization of Nisin loaded hydrogel network could be envisaged as a potential drug delivery platform for oral infections. Nisin loaded PVA-Alginate biocompatible hydrogel exhibited apparent swellable, flexible, nonhaemolytic materials and active antimicrobial and nontoxic materials. Physicochemical properties of these Nisin loaded PVA-Alginate biocompatible hydrogels have great potential in biomaterial-based drug delivery systems in controlling the growth and proliferation of major oro-dental pathogens. This could be exploited for the temporary biocompatible dental filling materials to treat the caries. Exploring potential nisin loaded hydrogel delivery systems will provide a brighter future of more friendly, effective and personalized treatment to deal with dental caries.