This study was designed to evaluate the effect of high pressure processing (HPP) on the microbiological safety and quality of sliced raw squid during refrigerated storage. The sliced and vacuum-packed raw squid samples were treated at 200, 300, and 400 MPa for 20 min by using a custom-made high pressure processor. The numbers of psychrotrophic bacteria in the sliced raw squids treated at 200, 300, and 400 MPa were reduced by 0.5, 2.5, and >4.7 log CFU/g, respectively. The amounts of trimethylamine (TMA) produced in the sliced raw squids were reduced by 20, 33, and 51% at 200, 300, and 400 MPa, respectively, as compared to the control. The amount of total biogenic amines (BAs) in the control significantly increased up to 1.70 mg/g after 10 days of refrigerated storage, while that in the 400 MPa-treated squid sample gradually increased up to 1.33 mg/g. The autolytic activity values in the control, 200, 300, and 400 MPa-treated squid samples were 4.70, 2.28, 2.18, and 1.55 nkat/g, respectively, after 20 days of refrigerated storage. The HPP effectively retarded the microbial growth, TMA formation, autolytic activity in the sliced raw squids. Therefore, the HPP could be used as an effective processing tool for improving microbiological safety and quality of seafood.