Intestinal coccidiosis caused by Eimeria protozoan species is an economically important disease, especially in poultry and cattle. Anti-coccidial drugs commonly used for controlling coccidiosis are toltrazuril (TTZ) and diclazuril (DCZ). In this study, the efficacies of TTZ and DCZ were compared using a murine model, and the effect of these treatments on the induction of acquired resistance was evaluated. Male C57BL/6J mice were inoculated with 1,000 sporulated E. vermiformis oocytes and treated with TTZ or DCZ. The recommended TTZ dose for cattle (15 mg/kg) completely prevented oocyte excretion. But, mice required 5 mg/kg of DCZ, which is five times the recommended dose for cattle, to reduce oocyte excretion. In E. vermiformis re-infection, TTZ (15 mg/kg) and DCZ (5 mg/kg) treatments did not interfere with the development of acquired resistance. Bodyweight gain was significantly higher in the TTZ-treated group than in the control (untreated/infected) group and the DCZ-treated group, and no significant difference in bodyweight gain was observed between the TTZ-treated group and the healthy (uninfected/untreated) group. Analysis of T lymphocyte subsets in the spleen and mesenteric lymph nodes indicated that the relative populations of CD4+ and CD8+ T cells were reduced in the DCZ-treated and control (untreated/infected) groups, suggesting there was immunosuppression during the infection. However, no reductions in T cell populations were observed in the TTZ-treated group. The results indicated that an optimal anti-coccidial drug is one that can completely break the parasite life cycle in the host animal.