Abstract: Rapid-acting antidepressants (RAADs) can alleviate depressive symptoms within hours and provide a new therapeutic strategy for major depressive disorder, particularly treatment-resistant depression. Representative RAADs such as ketamine and esketamine exert their rapid antidepressant effects mainly by restoring glutamatergic/GABAergic balance, enhancing AMPA receptor-related signaling, activating the BDNF-TrkB-mTORC1 pathway, and promoting synaptic plasticity. In recent years, the eukaryotic elongation factor 2 kinase (eEF2K)/eukaryotic elongation factor 2 (eEF2) axis has attracted increasing attention as a key molecular link between receptor signaling and translational elongation. Previous studies have mainly focused on the canonical model in which inhibition of eEF2K and dephosphorylation of eEF2 relieve translational repression. However, this model does not fully account for the shared features of different RAADs in translational selectivity, spatiotemporal specificity, and multi-pathway integration. An eEF2-centric analytical perspective is proposed based on current clinical and mechanistic advances in RAAD research, with emphasis on the potential roles of eEF2 in local translational regulation, brain-region-specific plasticity, and multi-pathway integration. In combination with our group’s preliminary work, the potential research value of eEF2 as an intervention node for rapid-acting antidepressants is further discussed. Direct experimental evidence involving eEF2 remains mainly confined to the NMDAR/eEF2K/eEF2 pathway and to animal and cellular studies, and its generalizability across different types of RAADs, as well as its druggability, remains to be further validated.