Rationale <p>18β-Glycyrrhetinic acid (18β-GA) exhibits antidepressant-like effects in mice, but the underlying mechanisms remain unclear.</p> Objective <p>This study aimed to explore the role of serum polyunsaturated fatty acids in the antidepressant-like effects of 18β-GA.</p> Results <p>18β-GA exerted antidepressant-like effects in mice susceptible to chronic social defeat stress (CSDS). These effects were associated with increased serum levels of docosahexaenoic acid (DHA), neuroprotectin D1 (NPD1), and N-docosahexaenoylethanolamide (DEA), alongside decreased levels of 14,15-dihydroxyeicosatrienoic acid (DHET). Additionally, 18β-GA restored the suppressed brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway and reduced the elevated pro-inflammatory cytokine levels in CSDS-susceptible mice.</p> Conclusions <p>This study demonstrates that the antidepressant-like effects of 18β-GA in CSDS-susceptible mice are closely associated with DHA and its metabolites.</p>