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Sarcomphalus joazeiro (Mart.) is a promising candidate for the formulation of new therapies against parasitic infections. This study aimed to quantify the content of phenolic compounds and evaluate the antioxidant, antileishmanial, and cytotoxic potential of ethanolic extracts of the leaves (EELSJ) and bark (EEBSJ) of S. joazeiro. Quantification of phenolic acids (caffeic acid, p-coumaric acid, ferulic acid, cinnamic acid) and flavonoids (naringenin, pinocembrin, and apigenin) was performed by high-performance liquid chromatography with a diode array detector (HPLC-DAD). The extracts were subjected to antioxidant assays, including Fe3+ reduction, Fe2+ chelation, and inhibition of oxidative degradation of deoxyribose (2-DR). The antileishmanial activity was evaluated against promastigote forms of Leishmania amazonensis, while cytotoxicity was assessed in J774.G8 macrophages. Among the biological effects evaluated, EELSJ showed potent hydroxyl radical (•OH) scavenging activity, with IC50 < 10 µg/mL, which potentially correlates with its phenolic acid and flavonoid content (0.7066 mg/g). In comparison, EEBSJ showed a lower phenolic content (0.197 mg/g) and demonstrated Fe2+ chelating activity (IC50 = 14.96 ± 0.0477 µg/mL). EELSJ also exhibited antileishmanial activity against L. amazonensis (IC50 = 246.20 µg/mL), with low cytotoxicity (CC50 = 343.3 µg/mL; SI = 1.39), whereas EEBSJ showed minimal antileishmanial effect and marked cytotoxicity toward J774.G8 macrophages (CC50 = 5.866 µg/mL). The leaves of S. joazeiro stand out as the most promising plant organ for future investigations. Future studies should focus on investigating their action mechanisms in more detail.