The optimal preparation process of polyethylene glycol-modified luteolin liposome was investigated to enhance the bioavailability of luteolin. Polyethylene glycol-modified luteolin liposomes were prepared by the thin-film dispersion method. Phospholipids, cholesterol and phosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000) were employed as carriers, and the encapsulation efficiency was used as the evaluation index. The Box-Behnken design experiment was used to optimize the process parameters by response surface optimization method. Then the size, zeta potential and morphology of the prepared liposomes were determined. Results showed that the optimal conditions were: ratio of membrane to material was 10:1, ratio of lipid to drug was 16:1, and mass fraction of DSPE-PEG2000 was 3%, ultrasonic treatment time was 15 min, and hydration temperature was 40 ℃. The average encapsulation efficiency of the modified luteolin liposomes was approximately 86.3%, with the mean particle size and potential being 134.1 nm and -14.07 mV, respectively. The cumulative release rates of luteolin from the liposomes in the simulated gastric juice, small intestinal juice and colon fluid were 39.08%, 43.67% and 71.71%, respectively. The prepared liposomes had a high encapsulation efficiency, uniform particle size and obvious sustained-release effect. The preparation method is simple and feasible.