For tissue engineering applications, porous/biocompatible scaffolds are crucial. Some novel composites, CuMOF@PDMS, were fabricated by incorporating Cu-MOF into a PDMS sponge. Then, a layer of chitosan was coated on the Cu-MOF@PDMS sponges by the dip-coating method. The nanocomposites can be benefited by the flexibility characteristic of PDMS, the porosity of the Cu-MOF, and the bactericidal activity of chitosan. Morphological and chemical characterization of the as-obtained materials were investigated using FT-IR, XRD, SEM, EDS mapping, and TEM techniques. The obtained results exhibited that Cu-MOFs and chitosan are attached to the PDMS surface. TEM analysis exhibited the incorporation of Cu-MOF nanoparticles on the PDMS surface. The effect of Cu-MOF and chitosan on the antibacterial activities and cytotoxicity of sponges were also studied. Chitosan enhanced the antibacterial efficacy of the Cu-MOF@PDMS sponges against Staphylococcus aureus and Escherichia coli. The Chitosan@Cu-MOF@PDMS sponge resulted in a marked decrease in the number of viable bacteria cells (> 4.5 log10 CFU). Biological studies exhibited that the experimented sponges including the CuMOF@PDMS and the Chitosan@Cu-MOF@PDMS scaffolds provided proper surfaces for cell adhesion, proliferation, and viability compared with the pure PDMS sponge. Additionally, the obtained results confirmed that the presence of the Cu-MOF and chitosan in the nanocomposites have significant importance in cell attachment and viability. The as-fabricated chitosan-coated Cu-MOF@PDMS sponges are green, biocompatible, and potential scaffolds for antibacterial and tissue engineering applications.