Cryptosporidiosis is an imperative global health concern. Unfortunately, Nitazoxanide (NTZ) (the nowadays drug of choice) is not effective in treatment of immunocompromised patients. We aimed to assess the possible anti-cryptosporidial prophylactic and therapeutic effects of Mefloquine (MQ) on infected immunosuppressed murine models. Mice were divided into five groups; GI: received Mefloquine (400 mg/kg/day), GII: received NTZ (100 mg/kg/bid), GIII: received a combination, half dose regimen of both drugs, GIV: infected untreated and GV: non-infected untreated. Each treated group was divided into three subgroups; Ga prophylaxis (PX), thereafter infection, Gb first and Gc second treatment doses. Assessment was done by parasitological, histopathological and serological techniques. A significant oocyst clearance was detected in all prophylactically treated groups. GIa showed 77% reduction of the mean oocyst count in stool while GIb and GIIIc showed100% oocyst clearance. Histopathologically, the ileocecal sections from GIV showed loss of brush borders with marked villous atrophy.GIa induced a moderate improvement of those pathological changes. Moreover, the villi in GIb and GIIIc retained their normal appearance with minimal inflammatory cells. Serum interferon gamma levels showed highly significant increases in GI&GIII compared to GIV while a nonsignificant increase was observed in GIIa only. On the contrary, serum interleukin-17 levels showed a highly significant down-regulation in all treated groups in comparison to GIV. This study proved a marvelous effect of MQ-PX on cryptosporidiosis in immunosuppressed mice and thus it could be introduced as one of the most promising re-purposed prophylactic and therapeutic anticryptosporidial agents.