Systemic isosporosis, previously atoxoplasmosis, is a significant cause of mortality in juvenile passerine birds. Recommended treatment regimens are empiric and vary in efficacy. The goal of this study was to determine the pharmacokinetics and pharmacodynamics of ponazuril for treatment of systemic isosporosis. Ponazuril, diluted with water to create an oral suspension (50 mg/ml), was administered (100 mg/kg) to 72 European starlings (Sturnus vulgaris) by a single dose via direct oral gavage (n = 24), a single dose injected into superworm larvae (Zophobas morio; n = 24), or a daily dose mixed with commercial dog food to top-dress feed for 5 d (n = 24). Peak plasma concentrations were 5.84, 2.46, and 9.13 µg/ml for the direct gavage, injected larvae, and top-dressed feed groups, respectively. With repeated dosing, mean plasma concentrations from the top-dressed feed group were maintained between 8.12 to 13.11 µg/ml. Results suggested ponazuril at a dosage of 100 mg/kg administered via direct gavage or top-dressed feed, but not via injected larvae, would exceed the concentrations needed to inhibit merogony of other apicomplexan parasites in cell culture (5 µg/ml). To assess the pharmacodynamics of this dose, seven passerine birds, red-vented bulbuls (Pycnonotus cafer; n = 2), blue-grey tanager (Thraupis episcopus; n = 1), and red-capped cardinals (Paroaria gularis; n = 4), were identified as shedders of systemic Isospora spp. via fecal qPCR. Birds were then treated with ponazuril (100 mg/kg) daily on top-dressed feed for 14 d. Fecal shedding was assessed via qPCR for 6 wk from the initiation of treatment. Treatment was associated with reduction in proportions of fecal shedding during the treatment period and the week following treatment, but shedding resumed in all birds by the end of sampling. Results support that treatment of breeding birds with 100 mg/kg ponazuril could reduce the shedding of active oocysts and decrease risk of clinical infection in susceptible juveniles.