Blue crab (Callinectes sapidus) is a highly valuable wild fishery species of crab native to the waters of the western Atlantic Ocean and the Gulf of Mexico. The annual commercial production of live blue crabs is approximately 50,000 metric tons with a dockside value of USD 200 million. Presently the US blue crab processing industry sells crab meat in three basic forms: fresh crab meat, pasteurized crab meat, and frozen crab meat. By far "Fresh" is the most desirable form of crab meat. However, fresh crab meat has a limited shelf life. This study evaluated the effects of high-pressure processing (HPP) on enhancing the microbiological quality and shelf life of blue crab meat. Live blue crabs were pressure-cooked in a retort (≥115 °C for 4-6 min). The crab meat was handpicked, packed in plastic containers with seals, subjected to HPP treatment, and stored at 4 °C. Container integrity and water leakage issues were examined by observation in addition to weight comparison before and after HPP treatment; the shelf life of crab meat with and without HPP treatments was examined via microbiological tests and sensory evaluations. Results show that polypropylene containers sealed with 10K OTR (oxygen transmission rate) film could withstand high pressure without water leakage issues; HPP treatment at 600 MPa for 3 min could extend the shelf life of fresh, cooked, and handpicked crab meat from 6 days to 18 days based on the strictest APC (aerobic plate account) limit (APC ≤ 100,000 CFU/g). The sensory quality of the HPP-treated crab meat was well accepted throughout the 3-week storage period. The results support the use of HPP as an effective non-thermal processing technology to enhance the microbiological quality and extend the shelf life of fresh RTE blue crab meat.