Cancer represents a form of unregulated cellular proliferation, persisting as a significant challenge to global health. Despite the progress made in therapeutic interventions, challenges such as inadequate drug selectivity, systemic toxicity, and the development of drug resistance continue to pose considerable obstacles. In response to these barriers, we prepared pH (Stimuli)-responsive gelatin (GA) nanocapsules (NCs) that encapsulate 5-fluorouracil (5-FU)-coated CuO-ZnO nanoparticles (NPs) to achieve a combined effect in anticancer activity. The CuO-ZnO nanoparticles have been chosen for their combined antitumor efficacy of CuO and ZnO NPs. CuO-ZnO NPs synthesized through an environmentally friendly approach utilizing Trichosanthes dioica fruit extract demonstrated a size of 35.79 ± 6.04 nm. The drug-coated NPs were encapsulated within a gelatin matrix, which was stabilized with poloxamer 188 (Po) through modified emulsion techniques. Various characterizations were conducted using FTIR, XRD, TEM, and XPS, yielding valuable insights into the structural integrity and morphology of CuO-ZnO NPs and NCs. The NCs' average size was found to be 331.4 ± 38.7 nm with an average zeta potential of -15.6 ± 4.98 mV. Studies found drug release is sensitive to acidic pH 5.6, with a more rapid release than pH 7.4 (~25% 48 h), increasing tumor delivery selectivity. The assessment of cytotoxicity (MTT assay) on HeLa cells revealed a markedly reduced IC (13.71 ± 2.6 µg/mL) for nanocapsules in comparison with CuO-ZnO NPs and 5-Fu, suggesting a combined interaction. The confirmation of the apoptosis feature was achieved via AO/EtBr staining. The results underscore the promise of PoGA-5Fu(CuO-ZnO) nanocapsules as a targeted approach to cancer therapy, demonstrating improved efficacy while minimizing systemic toxicity.