Four new highly oxidized caryophyllene-type sesquiterpenes (1–4), one new caryophyllene-type natural product (5), and two new drimane-type sesquiterpenes (6, 7), along with eight known compounds have been isolated from an endophytic fungus Pestalotiopsis adusta. Their structures were elucidated on the basis of HRESIMS, 1D and 2D NMR spectroscopic data analyses. The absolute configurations for 1 and 5 were determined by single-crystal X-ray crystallographic analysis using Cu Kα radiation. The absolute configuration of 6 was determined by CD spectrum associated with TD-DFT calculation of its benzoylated derivative 6a. The in vitro bioassay revealed that 8 and 9 presented cytotoxicity against cancer cell lines A549, HeLa, and SMMC-7721, in which 8 showed comparable activity (IC₅₀ = 28.3 μM) to the positive control etoposide (IC₅₀ = 23.2 μM) against SMMC-7721.