Cupressus sempervirens L. (Cupressaceae) is a species of cypress native to the eastern Mediterranean region. The ethanol extract of the powdered cones (fruits) of this plant, collected from Oxford, Mississippi during the fall of 2010, exhibited potent antimicrobial and antiparasitic activities. Bioassay-guided fractionation using a centrifugal preparative thin-layer chromatography yielded two potent antileishmanial and antimicrobial diterpenes, 6-deoxytaxodione (11-hydroxy-7, 9(11), 13-abietatrien-12-one) (1) and taxodione (2), together with ferruginol (3) and sugiol (4). Compounds 1 and 2 displayed potent antileishmanial activity with half-maximal inhibitory concentration (IC50) values of 0.077 µg/mL and 0.025 µg/mL, respectively, against Leishmaniadonovani promastigotes, compared to those of the standard antileishmanial drugs, pentamidine (IC50 1.62 µg/mL) and amphotericin B (IC50 0.11 µg/mL). Compounds 1–3 were also evaluated against L. donovani amastigotes in THP1 macrophage cultures. In addition, both 1 and 2 showed potent antibacterial activities (IC50 0.80 and 0.85 µg/mL) against methicillin-resistant Staphylococcus aureus. Compounds 1 and 2 had previously been isolated from Clerodendrum eriophyllum, where 2 showed potent cytotoxic activity. However, this is the first report of antimicrobial and antileishmanial activities of compound 1.