Calotropis gigantea (C. gigantea) extract with an ecofriendly nanotechnology approach could provide promising antimicrobial activity against skin pathogens. This study investigates the antimicrobial capability of green synthesized binary ZnO-CuO nanocomposites from C. gigantea against non-MDR (Staphylococcus aureus and Escherichia coli) and MDR (Klebsiella pneumoniae, Pseudomonas aeruginosa and methicillin-resistant S. aureus) skin pathogens. Scanning electron microscopy and transmission electron microscopy revealed the size and shape of B3Z1C sample. Results of X-ray powder diffraction, energy-dispersive spectroscopy, FTIR and UV-Vis spectroscopy analyses confirmed the presence of mixed nanoparticles (i.e., zinc oxide, copper oxide, carbon and calcium) and the stabilising phytochemical agents of plant (i.e., phenol and carbonyl). Antimicrobial results showed that carbon and calcium decorated binary ZnO-CuO nanocomposites with compositions of 75 wt% of ZnO and 25 wt% CuO (B3Z1C) was a strong bactericidal agent with the MBC/MIC ratio of ≤ 4 and ≤ 2 for non-MDR and MDR pathogens, respectively. A significant non-MDR zone of inhibitions were observed for BZC by Kirby-Bauer disc-diffusion test. Further time-kill observation revealed significant fourfold reduction in non-MDR pathogen viable count after 12 h study period. Further molecular studies are needed to explain the biocidal mechanism underlying B3Z1C potential.