Background: depression may be considered "the disease of the modern era". With a high prevalence worldwide causing significant morbidity and mortality and constituting a heavy burden on social and economic welfare. Despite decades-long research the exact pathogenesis of depression is still not fully understood. Aims: to investigate the behvioral deficits elicited by exposure to the combined model of lipopolysaccharide (LPS) then chronic mild stress (CMS) in male Wistar rats and to investigate the putative role of inflammatory cytokine production induced lipopolysaccharide exposure together with chronic stress in the pathogenesis of depressive like behaviour. Materials and Methods: Sixty five Male Wistar rats were divided into two groups; Control group (n=29): naïve rats left undisturbed, not exposed to stress and LPS/CMS exposed group (n=27). Results: exposure to LPS/CMS model induced a depressive-like behavior manifested by a decline in body weight gain, alongside an increase in immobility time in FST and a decrease in time of active interaction in SIT. Conclusion: this work highlights the depressive like behaviour induced by exposure to the combined model of lipopolysaccharide and chronic mild stress. This work also underscores the putative role of lipopolysaccharide exposure in modulating the stress-induced neuroinflammation which is thought to be crucial, not only for the pathogenesis of depression, but also for a wide array of neurological diseases.