The use of integrated plasma-activated water (PAW) with micro/nanobubbles (MNBs), ultraviolet (UV) photolysis, and ultrasonication (US) for the synergistic efficiency of Escherichia coli inactivation in chicken meat was investigated. A 2k factorial design was employed to optimize the combined treatment parameters for pathogen disinfection in Design of Experiments (DOE) techniques. Its effectiveness was evaluated based on electrical conductivity (EC), oxidation−reduction potential (ORP), hydrogen peroxide (H2O2) concentration, and E. coli inactivation. The most significant impact on E. coli reduction was observed for MNBs, UV treatment time, and their interaction (MNBs and UV). Optimal E. coli inactivation (6 log10 CFU/mL reduction) was achieved by combining PAW with MNB and UV for 10 and 20 min, respectively. Integrating PAW with appropriate supplementary technologies enhanced E. coli inactivation by 97% compared to PAW alone. This novel approach provides a promising alternative for pathogen control in chicken meat, potentially improving food safety and shelf life in the poultry industry.