Resveratrol (Res), a non-flavonoid polyphenolic compound extracted from natural plants, has many pharmacological effects such as anti-tumor, organ protection, improvement of cardiovascular disease, and anti-inflammation. However, due to its poor water solubility and light-degradable property, its bioavailability is restricted. In this study, the hyaluronic acid (Ha)-coated poloxamer 188 (F68) and poloxamer 407 (F127) and Ha-coated Res nanomicelles (Ha-F68/F127-Res-Mc) were prepared by film dispersion method. The nanomicelles were evaluated by indicators of encapsulation efficiency (EE), drug loading (DL), particle size, polydispersity index and zeta-potential. Besides, using the Box-Behnken design (BBD) based response surface methodology (RSM), obtained the optimum prescription process to obtain the Ha-F68/F127-Res-Mc. Compared with the Res active pharmaceutical ingredient (API), Ha-F68/F127-Res-Mc had higher water solubility and photostability, and could achieve sustained release. Compared with the Res active pharmaceutical ingredient (API), Ha-F68/F127-Res-Mc had higher water solubility and photostability, and could achieve sustained release. In conclusion, the prepared nanomicelles have stronger cytotoxic effect on MCF-7 than doxorubicin (DOX). This will provide a basis for the development of Res antitumor injection, and provide a reference for the research on nano-delivery systems of other BCS II drugs in the future.