Novel biodegradable micelles were synthesized by conjugating methoxy poly(ethylene glycol) (mPEG) to zein, a biodegradable hydrophobic plant protein. The mPEG–zein micelles were in the size range of 95–125 nm with a low CMC (5.5 × 10^–2 g/L). The micelles were nonimmunogenic and were stable upon dilution with buffer as well as 10% serum. Curcumin, an anticancer agent with multiple delivery challenges, was encapsulated in mPEG–zein micelles. The micelles significantly enhanced the aqueous solubility (by 1000–2000-fold) and stability (by 6-fold) of curcumin. PEG–zein micelles sustained the release of curcumin up to 24 h in vitro. Curcumin-loaded mPEG–zein micelles showed significantly higher cell uptake than free curcumin in drug-resistant NCI/ADR-RES cancer cells in vitro. Micellar curcumin formulation was more potent than free curcumin in NCI/ADR-RES cancer cells, as evidenced from the 3-fold reduction in IC₅₀ value of curcumin. Overall, this study for the first time reports a natural protein core based polymeric micelle and demonstrates its application for the delivery of hydrophobic anticancer drugs such as curcumin.