Oxidative stress contributes significantly to the development of neurodegenerative diseases, thus developing nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent neuroprotectors is highly required for either prevention or treatment of these diseases. This work highlights an electrophilicity-based strategy that allows finding more active Nrf2-dependent neuroprotectors than natural piperlongumine (PL). Electrophilic modification was applied on both the exocylic and endocyclic Michael acceptors of PL, which includes placement of an electron-withdrawing trifluoromethyl group on its aromatic ring in the ortho , meta , or para position to the exocyclic olefin, and further introduction of an electron-withdrawing α-chlorine on its lactam ring. From a panel of PL analogs, we identified PLCl-4CF 3 , characterized by the presence of p -trifluoromethyl group and α-chlorine, to be significantly superior to the parent PL in protecting PC12 cells from oxidative damage induced by 6-hydroxydopamine hydrochloride. Mechanistic studies reveal that the increased electrophilicity of PLCl-4CF 3 in its two Michael acceptors allows its ability to covalently modify Cys-151 at Keap1, facilitating inhibition against Nrf2 ubiquitination, translocation of Nrf2 into the nucleus, induction of phase 2 enzymes and final protection of PC12 cells from oxidative damage. [Display omitted] • Highlighting an electrophilicity-based strategy for designing Nrf2-dependent neuroprotectors. • Applying the designed piperlongumine analogs to illustrate the practical utility of this strategy. • Identifying PLCl-CF 3 as a promising lead molecule. • Rationalizing Nrf2-dependent neuroprotective mechanisms of PLCl-CF 3. [ABSTRACT FROM AUTHOR]