Chemoresistance encountered using conventional chemotherapy demands novel treatment approaches. Asplatin (Asp), a novel platinum (IV) prodrug designed to release cisplatin and aspirin in a reductive environment, has demonstrated high cytotoxicity at reduced drug resistance. Herein, we investigated the ability of green-synthesized nanocarriers to enhance Asp’s efficacy. Zinc oxide nanoparticles (ZnO-NPs) were synthesized using a green microwave-assisted method with the reducing and capping agent gambogic acid (GA). These nanoparticles were then loaded with Asp, yielding Asp@ZnO-NPs. Transmission electron microscopy was utilized to study the morphological features of ZnO-NPs. Cell viability studies conducted on MDA-MB-231 breast cancer cells demonstrated the ability of the Asp@ZnO-NPs treatment to significantly decrease Asp’s half-maximal inhibitory concentration (IC₅₀) (5 ± 1 µg/mL). This was further demonstrated using flow cytometric analysis that revealed the capacity of Asp@ZnO-NPs treatment to significantly increase late apoptotic fractions. Furthermore, in vivo studies carried out using solid Ehrlich carcinoma-bearing mice showed significant tumor volume reduction with the Asp@ZnO-NPs treatment (156.3 ± 7.6 mm³), compared to Asp alone (202.3 ± 8.4 mm³) and untreated controls (342.6 ± 10.3 mm³). The histopathological analysis further demonstrated the increased necrosis in Asp@ZnO-NPs-treated group. This study revealed that Asp@ZnO-NPs, synthesized using an eco-friendly approach, significantly enhanced Asp’s anticancer activity, offering a sustainable solution for potent anticancer formulations.