Cryptosporidiosis is a serious parasitic diarrheal disease linked to the occurrence of colorectal cancer in immunocompromised patients. The FDA-approved drug nitazoxanide (NTZ) achieved a temporary effect, and relapses occur.Annona muricataleaf is widely used in traditional medicine to treat a wide range of disorders, including antiparasitic and anticancer effects. So, this study aimed to investigateAnnona muricataleaf antiparasitic and anticancer properties compared to NTZ inCryptosporidium parvum(C. parvum) acutely and chronically infected immunosuppressed mice. A molecular docking analysis was performed to evaluate the effectiveness of some biologically active compounds that represented the pharmacological properties ofAnnona muricataleaf-rich extract towardC. parvumlactate dehydrogenase compared to NTZ. For the in vivo study, eighty immunosuppressed albino mice were classified into four groups as follows: group I: infected and treated withA. muricata; group II: infected and treated with nitazoxanide; group III: infected and received no treatment; and group IV: were neither infected nor treated. Furthermore, half of the mice in groups I and II received the drugs on the 10th day post-infection (dpi), and the other half received treatment on the 90th day post-infection. Parasitological, histopathological, and immunohistochemical evaluations were performed. The docking analysis showed that the lowest estimated free energy of binding of annonacin, casuarine, L-epigallocatechin, P-coumaric acid, and ellagic acid towardC. parvumLDH, were −6.11, −6.32, −7.51, −7.81, and −9.64 kcal/mol, respectively, while NTZ was −7.03 kcal/mol. Parasitological examination displayed a significantly high difference inC. parvumoocyst mean counts in groups I and II compared to group III (p-value < 0.001), with group I demonstrating the highest efficacy. The analyses of histopathological and immunohistochemical results revealed that group I showed restoration of the normal villous pattern without evidence of dysplasia or malignancy.A. muricataleaf has proved to be a reliable agent forCryptosporidiumtreatment. This paper argues for its promising use as an antiparasitic agent and for the prevention of neoplastic sequels ofCryptosporidiuminfection.