Two new sesquiterpenoids, lyratol C (1) and lyratol D (2), together with two known sesquiterpenoids, dehydrovomifoliol (3) and blumenol A (4), were isolated from the whole plant of Solanum lyratum. Their structures were established by spectroscopic analyses. In vitro, the four compounds showed significant cytotoxic activities against three human cancer cell lines, namely, HONE-1 nasopharyngeal, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells, and gave IC50 values in the range 3.7—8.1 μM.