Phytochemical investigation on Asterothamnus centrali-asiaticus afforded four new sesquiterpenes, asterothamnones A–D (1–4), and three new benzofuran derivatives (5–7) together with ten known compounds (8–17). Their structures were elucidated using 1D and 2D NMR and X-ray diffraction analyses. Compounds 1–4 were verified to be unusual eudesmane sesquiterpenes possessing 4,6-dien-3-one or 1,4,6-triene-3-one conjugated system. The absolute configurations of compounds 1–8 were established by means of calculated electronic circular dichroism (ECD). Furthermore, all isolates were evaluated for their cytotoxic and anti-oxidant activities. Results showed that 10, 12 and, 14 exhibited cytotoxic activity against HepG2 cancer cells and 14 displayed cytotoxicity against MGC-803 cancer cells. Compounds 10 and 17 showed anti-oxidant effect.