Abstract: Objective: In this work, the optimal preparation process parameters of selenium-curcumin nanoparticles (SeNPs@Cur) were explored and its protective effect on alcoholic liver injury was evaluated. Methods: On the basis of single factor experiment, with particle size as the index, curcumin dosage, molar ratio of V_C to Na₂SeO₃, reaction time and reaction temperature were selected as influence factors. The process parameters of SeNPs@Cur were optimized by response surface methodology, and its structure was characterized by scanning electron microscope (SEM), fourier transform infrared spectrometer (FT-IR) and energy dispersive spectrometer (EDS). The protective effect of SeNPs@Cur on ethanol-induced LO2 cell injury was investigated by MTT method. Results: The optimal conditions of SeNPs@Cur were list as follows: Curcumin dosage of 5.92 mg/mL, molar ratio of V_C to Na₂SeO₃ of 10.39:1, the reaction time of 1.98 h, and the reaction temperature of 34.00 ℃. Under these conditions, the SeNPs@Cur with a minimum size of (100.79±3.46) nm was obtained. The loading rate of curcumin and the selenium content in the sample were 12.80%±0.80% and 23.32%±0.07%, respectively. Further structural identification showed that the prepared SeNPs@Cur was dispersed spherical nanoparticles. Moreover, compared with the model group, after treatments with different dosages of SeNPs@Cur, the cell viabilities increased from 58.06%±0.43% to 71.43%±1.39%, 77.33%±3.54%, and 85.41%±4.61%, respectively, indicating that SeNPs@Cur had a protective effect on LO2 cells damaged by ethanol in a concentration-dependent manner. Conclusion: The SeNPs@Cur with anti-alcoholic liver injury effect was successfully obtained, which provided new technical means and theoretical reference data for formulation improvement and application of curcumin.