Hyperascyrins A-H (1-11) and four known compounds (12-15) were acquired from the air-dried aerial parts of Hypericum ascyron and were all identified as methylated polycyclic polyprenylated acylphloroglucinol derivatives. Their structures were established by NMR spectroscopy, experimental and calculated electronic circular dichroism (ECD) data, and comparison with established compounds. Compounds 8 and 9 showed protection against paracetamol-induced HepG2 cell damage at 10 μM. The neuroprotective activities of all compounds (10 μM) were evaluated, and compounds 1 and 8 exhibited mild neuroprotection against glutamate-induced toxicity in SK-N-SH cells.