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Metal–organic frameworks (MOFs) are a class of crystalline porous materials with outstanding physical and chemical properties that make them suitable candidates in many fields, such as catalysis, sensing, energy production, and drug delivery. By combining MOFs with polymeric substrates, advanced functional materials are devised with excellent potential for biomedical applications. In this research, Zeolitic Imidazolate Framework 8 (ZIF-8), a zinc-based MOF, was selected together with cellulose, an almost inexhaustible polymeric raw material produced by nature, to prepare cellulose/ZIF-8 composite flat sheets via an in-situ growing single-step method in aqueous media. The composite materials were characterized by several techniques (IR, XRD, SEM, TGA, ICP, and BET) and their antibacterial activity as well as their biocompatibility in a mammalian model system were investigated. The cellulose/ZIF-8 samples remarkably inhibited the growth of Gram-positive and Gram-negative reference strains, and, notably, they proved to be effective against clinical isolates of <i>Staphylococcus epidermidis</i> and <i>Pseudomonas aeruginosa</i> presenting different antibiotic resistance profiles. As these pathogens are of primary importance in skin diseases and in the delayed healing of wounds, and the cellulose/ZIF-8 composites met the requirements of biological safety, the herein materials reveal a great potential for use as gauze pads in the management of wound infections.