Depression is an inflammatory, commonly occurring and lethal psychiatric disorder having high lifetime prevalence. Preclinical and clinical studies suggest that activation of immuno-inflammatory and oxido-nitrosative stress pathways play major role in the pathophysiology of depression. Honokiol (HNK) is a biphenolic neolignan possessing multiple biological activities including antioxidant, anti-inflammatory, anxiolytic, antidepressant and neuroprotective. The present study investigated the effect of HNK (2.5 and 5 mg/kg, i.p.) pretreatment (30 min prior to LPS) on lipopolysaccharide (LPS) (0.83 mg/kg, i.p.) induced depressive like behavior, neuroinflammation, and oxido-nitrosative stress in mice. HNK pretreatment at both the doses significantly attenuated LPS induced depressive-like behavior by reducing the immobility time in forced swim and tail suspension test, and by improving the anhedonic behavior observed in sucrose preference test. HNK pretreatment ameliorated LPS induced neuroinflammation by reducing IL-1β, IL-6 and TNF-α level in hippocampus (HC) and prefrontal cortex (PFC). HNK pretreatment prevented LPS evoked oxidative/nitrosative stress via improving reduced glutathione level along with reduction in the lipid peroxidation and nitrite level in HC and PFC. Pretreatment with HNK also prevented the increase in plasma corticosterone (CORT) and decrease in hippocampal BDNF level in LPS challenged mice. In conclusion, current investigation suggested that HNK pretreatment provided protection against LPS-induced depressive like behavior which may be mediated by repression of pro-inflammatory cytokines as well as oxido-nitrosative stress in HC and PFC. Our results strongly speculated that HNK could be a therapeutic approach for the treatment of depression and other pathophysiological conditions which are closely associated with neuroinflammation and oxido-nitrosative stress.