Background: Cryptosporidiosis consists in acute gastrointestinal infections in young children and is one of the two main leading causes of diarrhea in newborn calves in France and England resulting in substantial financial losses for farmers and a source of contamination for humans. Despite the seriousness of cryptosporidiosis and the recent strong mobilization of the scientific community to find for new therapeutic strategies (eg Swale et al. PMID: 31694928), the obtention of new potent drugs targeting these pathogens is still urgently awaited. Objective: Identification of new potent orally active anti-Cryptosporidium compounds able to prevent and control an established infection in order to increment the poor number of therapeutics available. Material and Methods. A targeted library of approximately 1000 compounds was initially screened for anti-Cryptosporidium activity leading to the identification of 3 compounds with a best EC50 around 700 nM. Medicinal chemistry guided by structure activity relationship (SAR) via in vitro assays in HCT-8 cell cultured with transgenic Cryptosporidium was applied to optimise efficiency. Best compounds from in vitro selection were evaluated as oral therapeutics in mouse models (neonatal mice, IFNγ-/-) and neonatal lambs. Results: Successive in vitro assays following chemical improvement allowed to identify several drugs active in the nanomolar range, with the best candidates with EC50 in low sub nanomolar range. Both mice models and lamb experiments confirmed the strong efficacy (parasite load; weight gain) of these soluble and orally administrable compounds. No adverse effects were detected in the in vivo experiment. Conclusion: The strong efficacy of the best compounds combined to low toxicity revealed their robust selectivity for Cryptosporidium, thus revealing the strong potential of these new therapeutics which hopefully will be able to participate in the future arsenal of therapeutics required for optimal cryptosporidiosis control.