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The phytochemical investigation of the crude ethanol extract of the leaves of Nectandra megapotamica afforded three new (2d, 3b, and 3c) and eight known (1a−d, 2a−c, and 3a) tetrahydrofuran lignans. Regarding the in vitro trypanocidal activity, the lignan-rich fraction, at a concentration of 2.0 mg/mL, was 100% active. Compound 1a was the most active, showing an IC₅₀ value of 2.2 μM and lysis of 94% of the parasites at 32 μM. Compounds 1b, 1d, 2a, 2c, and 3a displayed moderate activity, while compound 1c was inactive.