A pair of new flavan derivative enantiomers (1a and 1b), four new drimane sesquiterpene lactones (2-5) and a known compound (6) were isolated from Inonotus obliquus. Their structures were determined by comprehensive spectroscopic analyses. Compounds 1a/1b were separated by chiral chromatographic column successfully. The absolute configurations of compounds 1-5 were determined by comparison of their experimental and calculated ECD spectra. Notably, compounds 1a/1b represented the first pair of enantiomers in nature with tetrahydrofuran-flavan skeleton. A plausible biosynthetic pathway for (±)-1 was also proposed. All isolates were evaluated for their neuroprotective activities against HO-induced cell injury in SH-SY5Y cells. The results showed that compound 2 exhibited moderate neuroprotective activity at the concentration of 25.0 µM.