Developing simple and energy-saving pathways to prepare high-efficient and robust non-noble metal based electrocatalysts remains a huge challenge to hydrogen production from seawater electrolysis. Here we demonstrate a facile hydrothermal-calcination-etching approach that simultaneously achieves the required surface N doping and Fe vacancies generation to activate the Ni-O-Fe active motifs in N-vFe-NiFe2O4/NF. The unique localized environments (Ni-N-Fe structures and unsaturated O- and N-coordination) due to dual-defect strategy can effectively regulate the electronic structure of the Ni-O-Fe motif to make the motif more reactive. As a result, the N-vFe-NiFe2O4/NF catalyst exhibits overpotentials of 210, 213 and 222 mV to deliver 100 mA cm−2 in 1.0 M KOH, simulated seawater and alkaline seawater environments, respectively. Theoretical calculations prove that the Ni-O-Fe structure is the active motif and that the presence of special localized environments can optimize the adsorption of key intermediates on the activated active motifs.