In this study, zwitterionic poly(sulfobetaine acrylamide) (pSBAA) nanocomposite hydrogels were synthesized and implemented as effective chronic wound dressings. The hydrogels exhibited reinforced mechanical properties from added hectorite nanoclay as a physical crosslinker in the polymer chains. Due to the strong interaction with water molecules via ionic solvation, the hydration of the zwitterionic nanocomposite hydrogels was superior to the non-ionic 2-hydroxyethyl methacrylate (pHEMA) hydrogels, which interacts with water molecules via hydrogen bonding. The pSBAA nanocomposite hydrogels cytotoxicity was accessed with NIH-3T3 fibroblast by the MTT assay, the results indicated negligible cytotoxicity after incubation for three days. In addition, the zwitterionic hydrogels displayed evident resistance to adsorption of bovine serum albumin (BSA), NIH-3T3 fibroblast, and bacteria of gram positive S. epidermidis and gram negative P. aeruginosa. The need for antifouling properties in a wound dressing is because commercial dressings removal typically damaging newly formed tissues and colonization of microorganisms occurs on the dressings. For clinical applications as wound dressings, we created normal and diabetic wounds on mice and compared newly developed pSBAA nanocomposite hydrogels with commercial available products. We demonstrated that non-adhesive pSBAA nanocomposite hydrogels enabled ready wound surface removal. Moreover, the wound recovery was conducted with normal and diabetic wounds on rat dorsal by visual observation and showed a complete heal after 10 and 12 days, respectively. Moreover, the histological examination of mice skin confirmed that the zwitterionic hydrogels exhibited thorough re-epithelialization and total formation of new connective tissues in the normal and diabetic wounds after 10 and 12 days, respectively, which was faster than commercial dressings. Consequently, we demonstrated that the pSBAA nanocomposite can serve as an effective dressing for wound management.