In this study, we investigated a new method for rapid brewing of fish sauce by ultrasound-assisted enzymatic digestion of the skin of Thamnaconus septentrionalis. The optimal conditions for ultrasound-assisted enzymatic digestion of fish skin were explored by response surface experiments. Then, the effects of seed koji content, salt addition, and temperature on fermentation were investigated by orthogonal tests. The results showed that the optimal conditions for ultrasound-assisted enzymatic digestion of fish skin were: ultrasonic power of 195 W, enzyme addition of 3000u/g, the temperature of 60°C, and time of 7 h; the optimal conditions for fermentation were: 20% of seed koji addition, 15% of salt added, and temperature of 40°C. After 7 days of fermentation under these conditions, the amino acid-N content of the fish sauce was 0.48 ± 0.002 g/100 g, the total nitrogen content was 0.85 ± 0.002 g/100 g, the acidity was 0.37 ± 0.03 g/100 g, and the pH was 5.87 ± 0.14. Novelty impact statement In this study, a new method of preparing fish sauce by ultrasound-assisted enzymatic digestion of Thamnaconus septentrionalis skin was explored. The method shortened the time of fish sauce preparation to one week.