A novel pH-responsive, chemically crosslinked hydrogelator (cl-β-CD/pVP) has been fabricated using β-cyclodextrin (β-CD) and N-vinyl pyrollidone (N-VP) in presence of diurethane dimethacrylate (DUDMA) crosslinker/azobisisobutyronitrile initiator through free radical polymerization. Various grades of cl-β-CD/pVP have been synthesized and the best grade has been considered with higher crosslinking density, higher gel strength, and lower % swelling ratio. The hydrogelator has been characterized by FTIR, 1H and 13C NMR spectroscopy, TGA, and FESEM analyses. The hydrogelator demonstrates pH-responsive behavior, which has been confirmed by swelling behavior and gel characteristics at various pH (at 37 °C). Using hen egg lysozyme, degradation experiment has been performed, which confirms the biodegradable nature of the hydrogel. The in vitro cytotoxicity study and live–dead assay suggest that the hydrogelator is cytocompatible toward MG-63 cells. Finally, the hydrogelator shows excellent efficacy as an antibiotic (amoxicillin) carrier. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018, 135, 45939. © 2017 Wiley Periodicals, Inc.