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Background and Aim: Piroplasmosis is a serious disease that infects animals, inflicting significant economic losses in the livestock industry and animal trade worldwide. Anti-piroplasm drugs now on the market have demonstrated host toxicity and parasite resistance. As a result, developing more effective and safer anti-piroplasm drugs becomes an urgent issue. This study aimed to evaluate the inhibitory effect of Capsicum annuum methanolic extract (CA) against the growth of Babesia bovis , Babesia divergens , Babesia caballi , and Theileria equi in vitro and against B. microti in mice., Materials and Methods: Fluorescence-based SYBR Green I assay was used to evaluate CA's inhibitory effect in vitro and in vivo when used either as a monotherapy or combined with diminazene aceturate (DA). The hematological parameters (HCT, hemoglobin, and red blood cells counts) were determined in the blood of mice every 96 h using Celltac a MEK-6450 electronic hematology analyzer., Results: The in vitro growth of B. bovis , B. divergens , T. equi , and B. caballi was inhibited by CA in a dose-dependent manner with IC 50 values of 4.87±1.23, 44.11±8.03, 8.23±2.54, and 1.26±0.50 mg/mL, respectively. In B. microti -infected mice, a combination therapy consisting of CA and a low dose of DA showed a significant (p<0.05) inhibition of B. microti growth nearly similar to those obtained by treatment with the full dose of DA., Conclusion: The obtained results indicate that CA might be a promising medicinal plant for treating babesiosis, especially when used with a low dose of DA., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Rizk, et al.)