Background: Considering low efficacy, and high toxicity of the commonly used drugs in cryptosporidiosis, in addition to the development of drug resistance, trial for a novel approach is required. Objective: To evaluate the efficacy of Nifuroxazide (Antinal), Trimethoprim-Sulfamethoxazole (Septrin), Nitazoxanide (NTZ), loaded-on copper-benzene tricarboxylate (Cu-BTC) metal organic frameworks (MOH) for treatment of Cryptosporidium-experimentally infected mice. Material and Methods: Ninety male Swiss albino mice were divided into nine groups. Except for the 1st group (control negative), all mice were infected with 103 Cryptosporidium oocysts. Except for 2nd group (infected non treated), the remaining groups of infected mice were administered the tested drugs 2nd day post infection (PI) for 7 days. Daily stool examination for oocyst shedding from day 3 to 18 PI was conducted to evaluate drugs’ efficacy. Furthermore, to confirm Cryptosporidium complete eradication, real time PCR (RT-PCR) was performed on stool samples collected after 3 weeks PI. Survival rate was also calculated for 3 weeks PI (at 7th, 14th and 21st d) to detect drugs’ efficacy. Besides, physical characterization and toxicity of Cu-BTC were performed before mice treatment. Results: Electron micrographs revealed 300-500 nm pyramidal crystals of Cu-BTC. Non-loaded Antinal, Septrin, and NTZ showed 67.2%, 62.2% and 76.6% reduction in oocyst shedding, while loaded drugs showed 88.4%, 66.7%, and 98.3% reduction, respectively. Additionally, RT-PCR revealed that the best treatment for cryptosporidiosis was NTZ@Cu-BTC, followed by antinal@Cu-BTC. Interestingly, using CuBTC alone had a relative positive therapeutic effect. Concerning the survival rate, Cu-BTC alone had 90% total survival that increased to100% when Cu-BTC was incorporated with studied drugs in all treated groups. Conclusion: The results indicated that Cu-BTC is an efficient delivery system that improved the efficacy of the commonly used drugs.