Background and Purpose: Neuroprotective strategy targeting ferroptosis is currently considered a promising therapeutic approach for neurodegenerative diseases (NDDs). Herpotrichones showed potential the neuroprotective activity with low toxicity. The current study aimed to find new herpotrichone neuroprotectants and investigate their neuroprotective mechanism in vitro and in vivo. Experimental Approach: Comprehensive separation methods were used to isolate new herpotrichone analogues. The H2O2, RSL3, 6-OHDA-induced PC12 cells and LPS-induced BV-2 cells were used to assess the potential neuroprotective effect of compounds. UV-vis spectroscopy was used to determine the cell-free antioxidant and iron-chelating capacity. Western blotting, immunofluorescence, quantitative PCR, flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the activation of the antioxidative elements and the regulation of the ferroptosis factors in cell cultures and in zebrafish larvae. Key Results: Herpotrichone A (He-A) and a new herpotrichone analogue with a new pentacyclic 6/6/6/6/3 skeleton exhibited significantly the neuroprotective effect in cell cultures. He-A activated antioxidative elements and modulated SLC7A11 pathways. The decreased lipid ROS levels but increased GSH level showed the anti-ferroptosis effect of He-A. The increased cell viability in RSL3-induced PC12 cells and the improvement of locomotor in 6-OHDA-induced zebrafish larvae indicated that He-A possessed protective ability against neuronal damage. Conclusion and Implications: This study identifies a novel compound He-A that protects against neuronal damage through activating Nrf2 pathway to upregulate antioxidative elements and increasing the expressions of SLC7A11, FTL and FTH1 in vitro and in vivo, which supports the development of He-A as a new neuroprotective agent targeting ferroptosis.