Background: Depression is associated with high levels of pro-inflammatory cytokines and oxidative markers. Inhibition of neuroinflammation and oxidative stress is beneficial for depression prevention and/or therapy. Diallyl disulfide (DADS), an active compound in garlic oil, has been shown to inhibit neuroinflammation and oxidative stress. The purpose of this study is to investigate the role and mechanism of DADS in lipopolysacharide (LPS)-induced depression-like behaviors in mice.Methods: We used behavioral tests and biochemical analysis to illustrate the role and mechanism of DADS in depression regulation.Results: Similarly to imipramine (10 mg/kg), a clinical antidepressant, DADS (40 or 80 mg/kg), which was administered 1 h before LPS treatment (pre-LPS) or 1.5 h and 23.5 h after LPS treatment (post-LPS), prevented and reversed the LPS (100 μg/kg)-induced increase in immobility time in the tail suspension test (TST) and forced swim test (FST) in mice. Mechanistic studies revealed that DADS pre-treatment or post-treatment at the dose of 40 and 80 mg/kg prevented and reversed (i) the LPS-induced increases in interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) levels in the hippocampus and prefrontal cortex, (ii) the LPS-induced increases in contents of malondialdehyde (MDA), a parameter reflecting high levels of oxidative stress, as well as (iii) the LPS-induced decreases in contents of GSH, a marker reflecting weakened anti-oxidative ability, in both hippocampus and prefrontal cortexes in mice.Conclusions: DADS is comparable to imipramine in effectively ameliorating LPS-induced depression-like behaviors in mice, providing a potential value for DADS in prevention and/or therapy of depression.