In this work, the ultrasound-assisted enzymatic (UAE) conditions for salty compounds from Manila clam were optimized using a combination of fractional factorial design (FFD) and Box-Behnken design (BBD). The optimum protein extraction rate (40.13 ± 0.37), DH (25.92 ± 0.78), and salty score (4.01 ± 0.02) of salty extract were achieved with a solid-liquid ratio of 1:4 (w/w), hydrolysis temperature of 49 °C, and ultrasound time of 10 min. Sensory results showed that the UAE hydrolysates exhibited pronounced saltiness (6.25 ± 0.03) and umami (6.62 ± 0.03), with an impressively low detection threshold for salty taste at 69 mmol/L. The electronic tongue analysis revealed that the UAE hydrolysate had a distinct saltiness (3.73 ± 0.05), umami (8.96 ± 0.02) and richness (0.83 ± 0.00). The molecular weights of the peptides in the UAE solution were 84.497 Da, 211.710 Da, 380.530 Da, 568.644 Da and 830.696 Da, respectively. It was rich in alcohols, ketones and furans, and total of 79 volatile compounds (VOCs) were identified. After ultrasonic pretreatment, the content of organic acids was significantly increased, the content of succinic acid was 8.5 ± 0.24, and the content of malic acid was 4.68 ± 0.07. In conclusion, ultrasound-assisted enzymatic is an effective treatment for the extraction of salty compounds.