Both rosiglitazone and metformin have effects on blood glucose regulation and the proliferation of liver cancer cells. Combination therapy with these two drugs is common and effective for the treatment of diabetes in the clinic, however, the application of these two drugs is influenced by the poor dissolution of rosiglitazone and the gastrointestinal side-effect of metformin resulting from a high solubility. The formation of a multidrug crystal form (Rsg-Met) by a solvent evaporation method can solve the solubility issue. Crystal structure data and intramolecular hydrogen bonds were detected by X-ray diffraction and infrared spectroscopy. Surprisingly, Rsg-Met shortens the time spent in solubility equilibrium and multiplies the dissolution rate of Rsg. Finally, we found that a low concentration of Rsg-Met enhanced the proliferation inhibition effect on liver cancer cells (HepG2, SK-hep1) compared with rosiglitazone, without affecting the human normal cell line LO2.