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Although the role of adult hippocampal neurogenesis remains to be fully elucidated, several studies suggested that the process is involved in cognitive and emotional functions and is deregulated in various neuropsychiatric disorders, including major depression. Several psychoactive drugs, including antidepressants, can modulate adult neurogenesis. Here we show for the first time that the α2δ ligands gabapentin [1-(aminomethyl)cyclohexaneacetic acid] and pregabalin (PGB) [(S)-(+)-3-isobutyl-GABA or (S)-3-(aminomethyl)-5-methylhexanoic acid] can produce concentration-dependent increases in the numbers of newborn mature and immature neurons generated in vitro from adult hippocampal neural progenitor cells and, in parallel, a decrease in the number of undifferentiated precursor cells. These effects were confirmed in vivo, because significantly increased numbers of adult cell-generated neurons were observed in the hippocampal region of mice receiving prolonged treatment with PGB (10 mg/kg i.p. for 21 days), compared with vehicle-treated mice. We demonstrated that PGB administration prevented the appearance of depression-like behaviors induced by chronic restraint stress and, in parallel, promoted hippocampal neurogenesis in adult stressed mice. Finally, we provided data suggesting involvement of the α2δ1 subunit and the nuclear factor-κB signaling pathway in drug-mediated proneurogenic effects. The new pharmacological activities of α2δ ligands may help explain their therapeutic activity as supplemental therapy for major depression and depressive symptoms in post-traumatic stress disorder and generalized anxiety disorders. These data contribute to the identification of novel molecular pathways that may represent potential targets for pharmacological modulation in depression.