Stressful life events are thought to be triggering factors of numerous neuropsychiatric disorders, including anxiety and depression. However, the interactions between chronic unpredictable mild stress (CUMS) and immune stimulation have not been thoroughly investigated. In the present study, we evaluated the effects of lipopolysaccharide (LPS) challenge at different time points on CUMS-induced anxiety- and depression-like behaviors. At 1 day before, 18 or 35 days following the initial of CUMS, mice were intraperitoneally given a single LPS (0.1 mg/kg). Neurobehavioral and biochemical studies were performed at the indicated time points. LPS challenge had different effects on CUMS-induced anxiety- and depression-like behaviors depending on the timing of stimulation. When given 1 day before CUMS, LPS restored brain-derived neurotrophic factor level and reversed anxiety- and depression-like behaviors. When given at 18 days after the initial of CUMS, LPS seemed to promote the immune response and even induce a slight exacerbation of neurobehavioral performance, although the difference did not reach statistical significance. Intriguingly, when given at the end of CUMS, LPS reversed some of the anxiety- and depression-like behavior. Taken together, our study highlights the complex interaction between stress and immune challenge, suggesting therapies that modulate immune responses should be tailored to the immune status of the individual.