Objective: This study aimed to investigate the antidepressant effect of hydroxyl safflower yellow A on rats induced by lipopolysaccharide. Methods: The depression model of rats was established by intraperitoneal injection of LPS. The normal control group, the model group, the positive control group and the hydroxyl safflower yellow A groups with different doses were set up, and the depression like behavior of rats was evaluated. The contents of TNF-α, IL-1β, IL-6 and BDNF, 5-HT in serum of rats were determined, and the histopathological changes of hippocampus were observed. The protein expression of TLR/NLR signaling pathway was detected. Results: Compared with the depression model group, the horizontal movement, vertical movement and sucrose preference of rats in each dose group of hydroxyl safflower yellow A group were increased, while tail suspension and swimming immobility time were decreased (P＜0.01). the serum levels of BDNF and 5-HT were increased while the levels of TNF-α, IL-1β and IL-6 levels were decreased (P＜0.01). The protein expression levels of TLR2, NLRP1, NLRP3, ASC, TLR4 and Caspase-1 in hippocampus tissue were decreased (P＜0.01). Conclusion: Hydroxyl safflower yellow A can improve the depression-like behavior of rats induced by LPS, and the mechanism may be related to the inhibition of TLR/NLR signaling pathway.