The Ganoderma fungus has been revered for centuries in traditional Chinese medicine and foods with high nutritional value for its purported health benefits. The extracts of Ganoderma applanatum (Pers.) Pat. showed promising protective activity against neurological damage caused by scopolamine in zebrafish. Eleven highly oxygenated lanostane triterpenoids with one or more α, β-unsaturated conjugated moiety, including three previously undescribed compounds appterpenactones A–C (1–3), and a nor-abietane diterpenoid, ganorphenol (4), together with related congeners were obtained from the fruiting bodies of G. applanatum. The structures and absolute configurations of the previously undescribed compounds were elucidated by analysis of nuclear magnetic resonance (NMR) spectra, quantum chemical calculations of NMR and electronic circular dichroism spectra, and X-ray crystallographic data. Compound 1 shares an unusual 6/6/5/6/5 ring system scaffold, while compound 4 represents a rearranged aromatic diterpenoid with rare ortho-dimethyl groups. All compounds were evaluated for their neuroprotective activity in glutamate-induced mouse hippocampal neuronal cell line (HT-22 cells). Ganorphenol (4) and applanoic acid C (6) demonstrated significant neuroprotective activity in inhibiting glutamate-induced HT22 cell death. Biochemical assays suggest that applanoic acid C may exert protective effects by activating the Nrf2/HO-1 pathway. Moreover, the further mechanistic study revealed that ganorphenol (4) can exert neuroprotective effects through the PI3K-AKT-mTOR pathway. Collectively, comprehensive experiments and molecular docking studies demonstrated that compounds 4 and 6 are potential neuroprotective agents. These findings provide valuable insights into the actions of trace bioactive components from edible materials and contribute to the broader understanding of neuroprotective compounds.