The antiplasmodium assay-guided investigation of the roots, stem bark, and leaves of Persea americanaMill. led to the isolation of a new fatty alcohol, perseatriol (1), along with six known compounds (2–7). Their structures were elucidated based on the analysis of their NMR and MS data. All crude extracts and fractions exhibited good antiplasmodial activity on Plasmoduim falciparum3D7 with IC50values ranging from 0.76 to 10.5 μg/mL; they also displayed cytotoxicity against HeLa cells with low selectivity indexes (SIs). A preliminary Plasmodiumlactate dehydrogenase (pLDH) assay was also performed on the isolated compounds. 9,9′-Di-O-feruloyl-5,5′-dimethoxysecoisolariciresinol (4) turned out to be non-toxic and displayed the best activities on P. falciparumwith an IC50value of 0.05 μM, comparable to the reference drug chloroquine with an IC50value of 0.03 μM. Furthermore, besides compound 4, this work reports the first isolation of lutein (2) and scopoletin (3) from P. americana. The crude extracts of roots, stem bark, and leaves of P. americana, their fractions and compounds completely suppressed the growth of P. falciparum. The observed activity supports the use of P. americanain folk medicine for the treatment of malaria.