The chronic stress has been known to have profound effect on cognition and behavior of human and animal. Noise is one of the most common stresses encounters in daily life. Inhibitor of phosphodiesterase (PDE5) sildenafil modulates cell signaling and neuroplasticity by elevating cGMP. In the present study, the effects of sildenafil on the memory and neuroprotection in noise-induced stress animal model were investigated. Mice were exposed to noise for 4 hours every day up to the 14 days at 110dB. They were divided into following four groups; noise non-exposed sildenafil non-treated group (N-, S-), noised non-exposed sildenafil treated group (N-, S+), noise exposed sildenafil non-treated group (N+, S-), and noise exposed sildenafil treated group (N+, S+). The mice received sildenafil (15 mg/kg) orally 30 minutes before noise exposure and sildenafil non-treated group received oral saline. Behavior assessments were performed using novel object recognition (NOR) test and radial-arm maize (RAM) test. Norepinephrine and 5-HIAA, were measured with high performance liquid chromatography using plasma samples. Brain derived neurotrophic factor (BDNF), heat shock protein 70 (Hsp70), and phosphorylated tau (P-tau) was analyzed with western blotting and flow cytometry using single-cell suspension from hippocampus and the whole brain. In NOR test, (N+, S-) group showed significantly reduced discrimination index compared with (N-, S-) and (N+, S+) group. In RAM test, reduction of working memory errors following the noise exposure is significant in (N+, S+) group until the 9th day of noise exposure compared with (N+, S-) group. Plasma levels of norepinephrine and 5-HIAA were higher in both (N-, S+) group and (N+, S+) group compared with (N-, S-) and (N+, S-) group. Single cell suspensions of hippocampus showed that increased BDNF expression and decreased Hsp70 and P-tau level in (N+, S+) group compared with (N+, S-) group. Noise induced stress can cause spatial and non-spatial memory deficits that can be ameliorated by sildenafil treatment. Sildenafil may have protective effects against noise stress by elevating BDNF and lowering tau phosphorylation with cGMP formation and the HPA axis modulation. The potential application of sildenafil as the therapeutic agent for stress induced cognitive dysfunction will require further studies.