ABSTRACTSkin loss can be caused by accident, burn, trauma, chronic wounds, and diseases, which is severely aggravated by multidrug‐resistant bacterial infections. Soft hybrids based on biopolymers combined with silver nanoparticles (AgNPs) have potential applications as wound dressing supports and skin tissue repair. Thus, our study focused on the design, green synthesis, and comprehensive characterization of carboxymethyl cellulose (CMC–AgNP) nanocomposites for producing hydrogel membranes, with tunable physicochemical properties, cytocompatibility, and biocidal activity for potential application as wound dressing and skin repair. These nanocomposites were prepared using CMC with two degrees of carboxymethylation, distinct concentrations of citric acid (CA) crosslinker, and AgNPs by in situ chemical reduction, forming hybrid membranes by the solvent casting method. The results demonstrated that superabsorbent hydrogels were produced with swelling and degradation behaviors dependent on the concentration of CA crosslinker, degree of carboxymethylation of CMC, and content of AgNP in the matrices. Moreover, the Fourier transform infrared spectroscopy analysis evidenced that the CMC functional groups (e.g., COOH and OH) were directly involved in the chemical reactions for the formation of AgNPs and hydrogel crosslinking pathway. These nanocomposites were cytocompatible using in vitro 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyltetrazolium bromide cell viability assay with of human embryonic kidney cells. Conclusively, the CMC–AgNP nanohybrids demonstrated to be simultaneously non‐toxic combined with highly effective antibacterial activity against gram‐positive multi‐resistant wound/skin pathogens (Staphylococcus aureus) and moderate effect towards gram‐negative strains (Escherichia coli and Pseudomonas aeruginosa). © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018, 135, 45812.