Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide. Platinum(II)-based drugs, a cornerstone in CRC treatment, are often limited by significant side effects and suboptimal efficacy. Herein, we present a platinum(IV) prodrug nanoplatform (Pt(IV)–Cro NPs) designed to overcome these challenges through intracellular morphological transformation, enhancing therapeutic outcomes against CRC. Pt(IV)–Cro NPs are formed via the self-assembly of Pt(IV)–crocetin (Pt(IV)–Cro) and mPEG–crocetin (mPEG–Cro), driven by hydrophilic–hydrophobic interactions. These nanoparticles exhibit concentration-dependent morphology, transitioning from rod-shaped structures at lower concentrations to spherical forms at higher concentrations. Notably, Pt(IV)–Cro NPs undergo time-dependent morphological changes within cells. Upon uptake by CT26 cells, the nanoparticles retain a nanorod shape during the first hour but transform into spherical structures within 3 h. These morphological transitions contribute to a remarkable 141-fold reduction in the half-inhibitory concentration (IC50) against CT26 cells compared to cisplatin alone. Pt(IV)–Cro NPs induced 3.14-fold greater apoptosis, 51.2% mitochondrial depolarization, and 55.9% ROS elevation compared to cisplatin. In vivo studies in CT26 tumor-bearing mice reveal that Pt(IV)–Cro NPs significantly outperform cisplatin alone, reducing tumor growth by up to 8.08 times relative to controls. This innovative nanoplatform combines enhanced efficacy with minimized side effects, offering a transformative approach to CRC therapy. The concentration-responsive self-assembly of Pt(IV)–Cro NPs and the occurrence of morphologic transformations within the cell characterize a major advancement in clinical CRC therapeutic strategies.