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The rapid development of aquaculture has led to an increase in price and high demand for fishmeal. Finding candidate protein sources for replacing fishmeal has become an urgent matter for the healthy and sustainable development of A. japonicus aquaculture. Therefore, we evaluated the effect of fishmeal subjected to enzymolysis (EF) and scallop mantle subjected to enzymolysis (ESM) by papain as a substitute for fishmeal on the growth, antioxidant activity and non‐specific immune response of A. japonicus. The results showed that EF and ESM did not lead to a difference in the growth performance of A. japonicus. However, the activity of respiratory burst and phagocytic increased in ESM group. The expression of Lysozyme (LZM) increased in the intestine of the EF and ESM group, while the expression level of superoxide dismutase (SOD) was reduced in the intestine and respiratory tree of the EF and ESM group. In conclusion, EF and ESM have no effect on the growth performance but could modulate the non‐specific immune responses of juvenile sea cucumber. Therefore, scallop mantle subjected to enzymolysis by papain is a candidate protein source for replacing fishmeal in the aquaculture of A. japonicus. [ABSTRACT FROM AUTHOR]