Using DH (degree of hydrolysis) as the main index, hydrolysis effects on Sipunculus nudus protein of seven proteases were compared. On the basis of single factor experiment, response surface methodology and Box-Behnken model were employed to establish the quadratic model for optimization the hydrolysis conditions. Results showed that the DH of Protamex was higher than those of others. The optimum hydrolysis conditions were as follows: the ratio of enzyme to substrate of 7.8%, hydrolysis time of 4 h and the hydrolysis temperature at 50 ℃. Under this condition, DH reached 24.81%. This study was aimed to provide theoretical basis for the development and utilization of S. nudus.