Objective: This study aimed to explore the effects and mechanism of Zan-Yu-Dan (ZYD) on the paroxetine-induced sexual dysfunction in rats. Methods: Total 50 male Wistar rats were divided into five groups, ten rats in each group. The rats in control group were treated with distilled water by intragastric administration; the rats in the model group were treated with 10 mg/kg paroxetine; the rats in the ZYD groups were administered with 10 mg/kg paroxetine and indicated doses of ZYD, respectively. After treatment for 4 weeks, sexual behavior parameters, testosterone levels, NO, cGMP, eNOS and PDE5 levels among all the groups were measured and compared. Results: Compared with model group, the mount latency (ML), intromission latency (IL) and ejaculatory latency (EL) in ZYD groups were significantly decreased with dose-dependent manner (P<0.05). The mount frequency (MF) in ZYD groups were significantly increased along with the dose-dependent manner (P<0.05). The intromission frequency (IF) in high and middle-dose ZYD group was increased significantly (P<0.05). After the treatment, serum testosterone, penile NO and cGMP levels in ZYD groups were increased significantly with the dose-dependent manner (P<0.05). In the model group, the expression level of eNOS was decreased while that of PDE5 was increased, while ZYD significantly increased the expression level of eNOS and decreased PDE5. Conclusion: Treatment with ZYD significantly alleviated paroxetine-induced sexual dysfunction by increasing serum testosterone levels and penile NO, cGMP and eNOS levels, reducing penile PDE5 level.