Cyclophosphamide (CTX), a broad-spectrum anticancer drug, kills cancer cells but also induces immunocompromise. The ameliorative effects of Acaudina leucoprocta peptides (ALPs) on CTX-induced immunocompromise in mice were investigated. Sixty male ICR mice were randomly divided into the normal group, model group (CTX), ALPS-L group (CTX+50 mg/kg ALPs), ALPS-M group (CTX+100 mg/kg ALPs), and ALPS-H group (CTX+200 mg/kg ALPs). An immunocompromised mouse model was established by administering CTX intraperitoneally for 5 days, followed by ALP administration for 19 days, after which the changes in immune indices and morphological changes of immune organs were detected. The results showed that the body weight of the high-dose ALP group increased to 36.10 g, which was only 0.37 g higher than that of the model group. The thymus and spleen indices were significantly increased (P<0.01), and the spleen morphology tended toward normal. The synthesis of nitric oxide (NO) in peritoneal macrophages, the level of serum hemolysin, and the activity of natural killer (NK) cells significantly increased (P<0.01). In addition, ALPs significantly increased the levels of cytokines and immunoglobulins in the serum of mice (P<0.01), and the levels of interleukin-1β (IL-1β) in the medium and high dose groups increased by 1.60 and 1.62 times, respectively. In conclusion, ALPs effectively ameliorated CTX-induced immunocompromise in mice and may serve as a natural source of immune enhancers.