Context: Croton cajucara Benth has been widely used in folk medicine, especially in the Amazonian region of Brazil, to treat several illnesses. Objectives: The objective of the study is to evaluate the stem bark hydroalcoholic extract (CC-EHA) of C. cajucara and their clerodane-type diterpene fractions (F1-7, F25-27, and F28) on promastigotes and axenic amastigotes of Leishmania amazonensis and trypomastigotes and epimastigotes of Trypanosoma cruzi. Materials and Methods: The extract was obtained in ethanol: water and the fractions with solvents of increasing polarity. The antiparasitic activities were assessed by 3,4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide method against promastigotes and axenic amastigotes from L. amazonensis in 24-h cultures and trypomastigotes and epimastigotes of T. cruzi in 72-h cultures. The experiments in triplicate were made in quadruplicate way in each time. The statistical tests used were t-Students and ANOVA. Results: Among those evaluated samples, the CC-EHA extract showed the higher antileishmanial activity of promastigote cultures (IC50 = 18.00 ± 0.01 μg/mL at 24 h). However, against axenic amastigotes, the polar fraction (F28), rich in diterpene transdehydrocrotonin (t-DCTN), showed the highest effect with an IC50 = 6.18 ± 0.02 μg/mL in culture of 24 h. In the T. cruzi assays, F28 also showed the greatest effect against trypomastigotes and epimastigotes, IC50 = 0.43 ± 0.02 μg/mL and 0.27 ± 0.02 μg/mL, respectively, at 72 h of culture. The results showed that the diterpene t-DCTN is the most important antiparasitic component in the hydroalcoholic extract obtained from C. cajucara, specifically against L. amazonensis and T. cruzi. Conclusion: Our results contribute to knowledge of these folk medicinal species as a promising antiparasitic phytotherapeutic alternative.