The aim of the present study is to develop an ecofriendly and cost-effective method for the synthesis and functionalization of copper oxide (CuO) nanosheets by chemical grafting of 3-(chloropropyl)triethoxysilane (ClPTES), p-aminothiophenol (ATP) and diethanolamine (DEA). Full characterization of the resulting materials through FTIR, X-ray diffraction (XRD), scanning–transmission electron microscopy (STEM) and energy-dispersive X-ray fluorescence (ED-XRF) allowed confirmation of the grafting of ClPTES, ATP, DEA, and CuO crystalline phase and assessment of the average size of the as-prepared CuO (500 nm) and its high purity, respectively. Cu functionalization was found to confer high catalytic activity in 4-nitrophenol (4-NP) reduction into 4-aminophenol (4-AP), methylene blue (MB) degradation, and decomposition of their mixture. Besides, DEA- and ATP-modified CuO also exhibited appreciable antibacterial capacity against Staphylococcus epidermidis and Escherichia coli. These results are of great importance because they provide the proof-of-concept that judicious modifications of mere CuO nanosheets provide low-cost polyfunctional materials with potential uses in catalysis and biomedical applications.