Background <p>Non-hormonal pharmacotherapies are widely used to manage depressive and anxiety symptoms in peri- and postmenopausal women, but comparative evidence across drug classes remains heterogeneous.</p> Objective <p>To systematically evaluate the efficacy and safety of non-hormonal pharmacological interventions for depressive and anxiety symptoms during the menopausal transition and postmenopause.</p> Methods <p>A systematic review of six databases and trial registries identified randomized and non-randomized studies evaluating SSRIs, SNRIs, gabapentinoids, and other pharmacotherapies. Due to substantial clinical and methodological heterogeneity, a structured Synthesis Without Meta-analysis (SWiM) approach was applied.</p> Results <p>A total of Thirty-one studies (<i>n</i> = 8,124 participants) were included. SNRIs showed more frequent positive effects on depressive symptoms compared with other pharmacological classes, while SSRIs demonstrated modest and variable effects. Gabapentinoids consistently improved vasomotor symptoms but showed limited and low-certainty effects on mood outcomes. Evidence for anxiety outcomes was inconsistent across all drug classes. Certainty of evidence ranged from very low to moderate.</p> Conclusions <p>Non-hormonal pharmacotherapies may provide benefit for mood symptoms during the menopausal transition and postmenopause, particularly SNRIs; however, conclusions are limited by heterogeneity, indirectness, and lack of head-to-head comparative trials.</p> Clinical trial number <p>Not applicable.</p>