The effectiveness of zinc oxide nanoparticles (ZnO-NPs) on Cryptosporidium parvum was investigated by infecting laboratory mice with a dose of 1 × 103 oocysts/mouse. Each group was given 1 mL of the specified dose and then administered ZnO-NPs at concentrations of 5, 15, and 20 mg/kg. The nested-polymerase chain reaction revealed the amplification of the heat shock protein gene of C. parvum in all samples that were identified microscopically using Ziehl–Neelsen staining. The current study indicated the use of ZnO-NPs as a treatment for mice infected with C. parvum oocysts for a week. The effects of the three concentrations varied in reducing the number of oocysts excreted in the feces of experimentally infected mice. The 20 mg/kg concentration was the best concentration becauseit completely reduced the oocysts on the fifth day, with a therapeutic efficiency of 100%. At this concentration, the mice completely stopped shedding oocysts compared to the positive control group, which continued to shed oocysts until the seventh day. This was also the closest concentration to the group treated with nitazoxanid, which achieved a therapeutic efficiency of 100% on the fourth day of treatment. At 15 mg/kg, therapeutic efficacy was achieved on the sixth and seventh days of treatment at a rate of 96.31% and 100% respectively. By contrast, 5 mg/kg showed low efficacy because the treated mice continued to produce oocysts until the seventh day of treatment.