Purpose <p>Controlled and effective drug delivery remained a significant challenge in oral drug therapy. This study was conducted to design novel stable ter-polymeric hydrogels-based delivery system for controlled and effective Loxoprofen sodium release and in turn to reduce side effects after oral administration.</p> Methods <p>Current study reports the development of novel pH responsive ter-polymeric NaAlg/Pec/PAA hydrogels with varied feed composition synthesized <i>via</i> free radical polymerization technique. Swelling analysis and drug release study was conducted in various phosphate buffer solutions. Pharmacokinetic analysis in rabbit model was conducted to investigate the drug plasma concentrations with time. FTIR and SEM analysis was conducted to explore the structural and morphological investigations of optimized ter-polymeric hydrogels.</p> Results <p>Concluded that ter-polymeric NaAlg/Pec/PAA hydrogels exhibited maximum swelling and drug release in basic pH environment (7.5) owing to ionization of carboxyl (-COOH) groups which makes them excellent drug carriers to colon. It was also found that with increasing polymeric contents and crosslinker, gel fraction and porosity of hydrogels increased. Drug release kinetics showed that ter-polymeric hydrogels followed zero order release with non-fickian mechanism. MTT assay confirmed that developed blank and drug loaded hydrogels are biocompatible and safe for oral administration. In vivo analysis in animal model showed that ter-polymeric hydrogels exhibited controlled drug release (C_max=2298.88 ng/ml) for 72&#xa0;h in comparison to free Loxoprofen sodium solution (C_max= 2337.50 ng/ml) for 40&#xa0;min. FTIR analysis confirmed the new ter-polymeric hydrogel structure while SEM analysis showed the porous hydrogel structure.</p> Conclusion <p>It is concluded from results that Loxoprofen sodium adverse effect can be effectively controlled after oral administration <i>via</i> encapsulating in ter-polymeric hydrogels.</p> Graphical Abstract <p></p>