Background: Cryptosporidiosis constitutes one of the most common causes of severe diarrhea in immunocompromised and malnourished individuals. It is considered as a life threatening for both of them. Objective: the present work aimed to assess the effect of priming with 102 Cryptosporidium parvum (C.parvum) oocysts on the immune response in the jejunum of experimental malnourished mice trying to restore the host immune defense against the parasite. Methodology: The experiment lasted for 23 days. Fifty (50) female Swiss mice aged 4weeks were randomly and equally divided into five groups: sham control; infected; malnourished; malnourished –infected and primed protected groups. All groups were followed for weight, oocyst shedding and intestinal parasite tissue load. At the end of the experiment, jejunums were collected and prepared for histological, morphometrical, immunohistochemical and cluster of differentiation CD4 & inducible Nitric Oxide Synthase (iNOS) gene expressions. Results: In compare to malnourished –infected group, primed protected group showed evident clinical, histopathological & immunological improvement. Body weight loss, oocyst shedding & parasite tissue burden were reduced in primed protected group. Also, an increase in iNOS and CD4 gene expressions and immune reactions in primed group reflected as an increased villous length and absence of dysplastic changes in the jejunum compared to malnourished –infected group. Conclusion: These outcomes deepen the insight of potential role of C. parvum priming on both innate and adaptive immunity in malnourished infected mice jejunum for further studies.