Significance Despite decades of research, the development of efficient strategies that can effectively deliver poorly water-soluble anticancer drugs remains a challenge. Hierarchical self-assembly strategy allows combining multiple therapeutic agents to produce a synergistic effect, thus enhancing the therapeutic efficacy. Herein we describe a hierarchical approach to solubilize a hydrophobic anticancer drug, curcumin in water via a combination of coordination-driven self-assembly and host–guest interactions. The water-soluble orthogonal self-assembly constructed by a hexagonal Pt(II) metallacycle, cucurbit[8]uril, and curcumin exhibited enhanced anticancer activity against melanoma and breast cancer cells compared with the corresponding precursors. This paper provides a platform for efficient delivery of hydrophobic anticancer drugs to cancer cells by the judicious implementation of multiple orthogonal interactions in a single process.