Ten undescribed highly oxidized sesquiterpenes and six known sesquiterpenes were isolated from H2O-soluble part of the fruits of Illicium lanceolatum A. C. Smith. The structures of undescribed compounds were elucidated by interpretation of spectroscopic data, and the absolute configurations of 2α-hydroxyneoanisatinic acid, (1R,5R,6S,7R,9R,10R)-3,4-dehydro-12-hydroxy-floridanolide, and (1R,4S,5R,6S,7S,9S)-1-deoxy-13-hydroxymerrilactone B were determined by the single-crystal X-ray diffraction analysis. Illilanceolatin A was the first example of a seco-prezizaane type sesquiterpene with a hemiacetal moiety located at C-10. 2α-Hydroxyneoanisatinic acid and anisatinic acid were two naturally occurring undescribed seco-prezizaane type sesquiterpenes with a 5/5/6 tricyclic carbon skeleton. Plausible biosynthetic pathways of the isolated polycyclic and highly oxidized sesquiterpenes derived from the intermediate allo-cedrane were proposed. (1R,5R,6S,7R,9R,10R)-3,4-dehydro-12-hydroxy-floridanolide, 1,3-dihydroxyneoanisatin, and 2α-hydroxyneoanisatin displayed neuroprotective effects with protection rates of 19.9, 22.7 and 24.3% at 10 μM, respectively. Additionally, the preliminary acute toxicity of anisatinic acid was also evaluated. Ten undescribed highly oxidized sesquiterpenes, along with six known analogues were isolated from the fruits of Illicium lanceolatum. Their neuroprotective, cytotoxic, anti-inflammatory, and antiviral activities were evaluated. Display omitted •Ten undescribed highly oxidized sesquiterpenes were isolated from the fruits of Illicium lanceolatum A. C. Smith.•Illilanceolatin A was the first example of a seco-prezizaane type sesquiterpene with a hemiketal moiety located at C-10.•Plausible biosynthetic pathways of sesquiterpenes derived from the intermediate allo-cedrane were proposed.