To extend the shelf life of chilled chicken, this study optimized the parameters for the synergistic effect of highpressure treatment and composite biological preservatives, developing an efficient preservation method. A four-factor interaction model was constructed using response surface methodology, with factors including Nisin concentration (0.4~0.5 g•L-1), lysozyme concentration (0.2~0.3 g•L-1), pressure (300~400 MPa), and holding time (10~20 min). The colony count and total volatile basic nitrogen (TVB-N) content were used as indicators to optimize the parameters. The optimal process conditions were determined as follows: Nisin concentration, 0.45 g•L-1; lysozyme concentration, 0.25 g•L-1; pressure, 350 MPa; and holding time, 15 min. Under these conditions, the colony count was 2.415 lg CFU/g and the TVB-N value was 7.845 mg/100 g, with ≤5% deviation between the predicted and experimental values. Storage experiments showed that the shelf life of chilled chicken could be extended to approximately 20 days. The results indicate that high-pressure treatment and biological preservatives have a synergistic effect, providing theoretical support for developing efficient preservation technologies for chilled meat products, and technical support for optimizing process parameters in industrial applications.