<h4>Background</h4>Histamine H3 receptor-targeting compounds modulate histaminergic tone and downstream monoaminergic/arousal circuits and have been proposed to exert potential antidepressant-like effects in preclinical models.<h4>Methods</h4>We conducted a systematic review and meta-analysis of rodent studies evaluating H3-related interventions on depression-like behavior. The gene discussed is HRH3; the disease is major depressive disorder.