Pt(IV) prodrugs have gained tremendous attention due to their indisputable advantages compared to cisplatin. Herein, new Pt(IV) derivatives with cinnamic acid at the first axial position, and inhibitor of matrix metalloproteinases-2 and -9, histone deacetylase, cyclooxygenase or pyruvate dehydrogenase at the second axial position are constructed to develop multi-action prodrugs. We demonstrate that Pt(IV) prodrugs are reducible and have superior antiproliferative activity with IC₅₀ values at submicromolar concentrations. Notably, Pt(IV) prodrugs exhibit highly potent anti-tumour activity in an in vivo breast cancer model. Our results support the view that a triple-action Pt(IV) prodrug acts via a synergistic mechanism, which involves the effects of CDDP and the effects of axial moieties, thus jointly leading to the death of tumour cells. These findings provide a practical strategy for the rational design of more effective Pt(IV) prodrugs to efficiently kill tumour cells by enhancing their cellular accumulation and tuning their canonical mechanism.