Squamate gastric cryptosporidiosis (SGC) is a common parasitic disease in captive snakes and is associated with substantial morbidity and mortality. Typical medications used to treat parasitic infections are ineffective against SGC. The purpose of this study was to evaluate new drug regimens for treating SGC in captive eastern indigo snakes (EIS; Drymarchon couperi). Twenty-six EIS naturally infected with Cryptosporidium serpentis were randomly divided into three groups: Group A (n = 9) received 10 mg/kg clofazimine in corn oil twice weekly by oral gavage for 6 wk; Group B (n = 9) received 5 mg/kg curcumin in corn oil twice weekly by oral gavage for 6 wk; and Group C (n = 8) received corn oil twice weekly by oral gavage for 6 wk as a control. Cloacal swabs were collected every 2 months for 6 months to measure C. serpentis shedding by probe hybridization quantitative polymerase chain reaction analysis (qPCR). Snakes that were qPCR negative after 6 months were immunosuppressed with a single dose of 4 mg/kg dexamethasone sodium-phosphate subcutaneously. These snakes were then screened by qPCR for an additional 6 months as described above. Prior to immunosuppression, 1/9 (11%) snakes from Group A, 2/9 (22%) snakes from Group B, and 2/8 (25%) snakes from Group C had tested qPCR negative. Following immunosuppression, all snakes were qPCR positive within 6 months. These findings suggest that 10 mg/kg clofazimine and 5 mg/kg curcumin administered orally twice weekly for 6 wk are ineffective in eliminating C. serpentis in naturally infected D. couperi.