In general, the poultry industry uses 0.5-1 ppm chlorine solution in the meat sanitization process. However, chlorine can react with organic material and produce halogenated organic compounds, notably chloroform, which causes bladder and rectal cancer in humans. For this reason, many industries try to avoid chlorine. This study investigated the efficacy of ultrasound and plasma-activated water (pAW) on the inactivation of Escherichia coli and Staphylococcus aureus in chicken muscle, rough skin, and smooth skin. Samples inoculated with bacteria suspension were treated by ultrasound alone and PAW-ultrasound. The Taguchi method and desirability function approach were used for the experimental design and optimization. Combined ultrasound and PAW inactivated up to 1.33 log CFU/ ml of E. coli K12 and 0.83 log CFU/ml of S. aureus at a sample thickness of 4 mm, at 40 °C for 60 min, while pAW alone only reduced E. coli K12 by 0.46 log CFU/ml and S. aureus by 0.33 log CFU/ml under the same condition. The muscle topography showed a porous structure, which facilitated the penetration of PAW. The color measurements of muscle treated with ultrasound and PAW-ultrasound were dramatically different from the untreated sample, as also perceived by the sensory evaluation panel. Therefore, the synergistic interaction of combined PAW-ultrasound could be used to enhance microbial inactivation in meat. In the past, sanitization by the chilling process with circulation system in the poultry industry used ice and 0.5-1 ppm chlorine to decrease the temperature of chicken carcass and lower the bacterial load in the gizzard and intestine. However, this process can cause cross-contamination because of circulated poultry water in the chiller tank. Additionally, chlorine can react with organic materials and produce halogenated organic compounds, notably, chloroform, which causes bladder and rectal cancer in humans. Various technologies have since been developed to reduce the bacteria in chicken meat, such as bacteriophage (ListShield ™) combined with UV-C light reduced Listeria monocytogenes 2.04 log CFU/ml 1 , ultrasound combined with a chemical immersion (lactic acid, sodium decanoate, and trisodium phosphate) reduced 0.73 log CFU/ml of Campylobacter jejuni, 1.02 log CFU/ml of TVC, and 1.37 log CFU/ml of total Enterobacteriaceae 2 , electrolyzed water reduced 1.0 log CFU/ml of microbial reduction 3 , non-thermal plasma jet with N 2 /O 2 gas reduced 0.66 log CFU/g of Salmonella typhimurium 4 , cold atmospheric plasma pen with He/O 2 gas reduced 3 log CFU/ml of L. innocua on muscle 5 , and dielectric barrier discharge plasma reduced 3.11 log CFU/ml of C. jejuni on skin 6. The past decade has focused on an environmentally-clean sanitizing technology called non-thermal plasma, particularly plasma-activated water (PAW). PAW can be used as a bacterial disinfection reagent in mass