Litchi (Litchi chinensis Sonn.) is a well-known traditional medicine since ancient times. The crude extract of litchi leaf exhibited good bioactivity against cancer cells. In this work, three sesquilignans, ehletianol C (1), sesquipinsapol B (2) and sesquimarocanol B (3), and one lignan glycoside schizandriside (4) were isolated from the ethyl acetate-soluble extract of litchi leaf by column chromatography. Their structures were further elucidated by ESI-MS and NMR spectral studies. Ehletianol C, sesquipinsapol B and sesquimarocanol B were detected from this species for the first time. Sesquipinsapol B (EC50 values less than 2.0 μg/mL) and sesquimarocanol B (EC50 values less than 2.4 μg/mL) showed very high cytotoxicities against nasopharynx carcinoma cells CNE1 and CNE2 cells, respectively. Thus, they could be utilized as good drug candidates against nasopharynx cancer. Moreover, three sesquilignans showed effective in vitro cytotoxicities against human cancer cells HepG2 and Hela. Four lignans showed better antioxidant activities than butylated hydroxytoluene (BHT).