Toxoplasmosis continues to be a public health problem, causing significant morbidity worldwide. Currently available medications, effective for acute toxoplasmosis, are nonetheless problematic due to adverse side effects in many patients. In addition, no medication is able to completely eradicate the parasite cysts, rendering infected individuals at risk for reactivation upon becoming immunocompromised. We examined the anti–T. gondii activity of 2 derivatives of artemisinin. In vitro metabolic stability tests revealed that both derivatives are stable in mouse plasma but only the thiazole CPH4-136 is stable in the presence of mouse microsomes. When tested in a mouse model of acute toxoplasmosis, both derivatives showed modest efficacy dependent upon the compound dose and the solvent vehicle. Finally, in a mouse model of chronic T. gondii infection, CPH4-136 at 3 mg/kg once per day for 32 days moderately but significantly decreased mouse brain cyst burden. Collectively, our findings suggest that artemisinin derivatives are partially effective in treating experimental T. gondii infections.