Depression is a recurrent neuropsychiatric disorder accompanied with other behavioral deficits, including memory impairment. A few studies have shown that methylene blue (MB) could promote cortical neurogenesis and exert neuroprotective effects on various brain diseases, including bipolar disorder. However, the potential antidepressant effects of MB have not been fully investigated. The present study was designed to investigate the effects of MB pretreatment on behavioral deficits and the underlying mechanisms in a lipopolysaccharide (LPS)induced depression mouse model. Mice were given saline (5 mL/kg) or MB (5, 20 mg/kg) intraperitoneally (i.p.) 30 min prior to lipopolysaccharide (LPS, 800 mu g/kg, i.p.) or the following behavioral tests. Thereafter, serum heme oxygenase 1(HO1) were determined by ELISA. The results showed that LPS significantly induced body weight loss and behavioral deficits that included increased floating time in the forced swimming test, increased immobility time in the tail suspension test, decreased sucrose preference in the sucrose preference test, and memory impairment in the novel object recognition (all p < 0.05) when compared with that of LPS-free mice. MB treatment significantly blocked most of these behavioral deficits induced by LPS when compared with that of mice in LPS-exposed groups. Furthermore, MB pretreatment prevented the LPS-induced decrease in serum level of HO1. These findings suggested that MB exerts rapidly neuroprotective effects in an LPS-induced depression mouse model, which may be involved in its regulation on the peripheral HO system.