Cryptosporidiosis is a diarrheal disease caused by the parasite Cryptosporidium resulting in over 100,000 deaths annually. Here, we present a structure-activity relationship study of the benzoic acid position (R6) of pyrazolo[3,4-d]pyrimidine lead SLU-2815 (1), an inhibitor of parasite phosphodiesterase CpPDE1, resulting in the discovery of benzoxaborole SLU-10906 (63) as a benzoic acid bioisostere. Benzoxaborole 63 is 10-fold more potent than 1 against the parasite in a cell-based infection model (EC50 = 0.19 μM) and non-cytotoxic. Furthermore, 63 has a fast rate of parasite-killing and is orally efficacious in a Cryptosporidium mouse infection model (50 mg/kg BID), although relapse was observed 7 days post-drug treatment. The partial selectivity profile versus human phosphodiesterases is preserved with the benzoxaborole motif and represents an important feature to improve in future optimization. Benzoxaborole 63 represents an important advance toward the optimization of the pyrazolo[3,4-d]pyrimidine series and the identification of a drug to treat cryptosporidiosis.