To investigate the inflammation-related mechanisms through which ketamine exerts antidepressant effects by inhibiting the ERK1/2/NF-κB signaling pathway. Methods: Fifteen normal rats were assigned to the blank control group (Group Blank). Chronic unpredictable stimulation was used to generate the depression rat model, and 45 successfully constructed depressed rats were randomly divided into three groups: control group (Group Con), placebo group (Group Place), and experimental group (Group Exp), with 15 rats in each group. Group Con was not given medication; Group Place was given placebo by oral gavage after successful model establishment; Group Exp was given ketamine by oral gavage for 21 days. Behavioral changes were detected by tail suspension test, forced swimming test, and novelty inhibition feeding test before and after treatment. The expression of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) in the hippocampus was detected by ELISA and qRT-PCR. Changes in signal molecules related to ERK1/2 and NF-κB inflammation in the hippocampus were detected by Western blotting. Results: Ketamine significantly shortened swimming immobility time (P<0.05) and tail suspension immobility time (P<0.01) in behavioral experiments. The expression of IL-1β, IL-6, and TNF-α in Group Con was significantly higher than that in Group Blank at both protein and mRNA levels. In addition, the expression of IL-1β, IL-6, and TNF-α in Group Exp was significantly lower than that in Group Con (P<0.05). The expression of pERK1/2 and pNF-κB in Group Con group was significantly higher than that in Group Blank, while the expression of pERK1/2 and pNF-κB in Group Exp group were significantly lower than that in Group Con (P<0.05). Conclusion: Ketamine can significantly improve the behavior of depressed rats by inhibiting inflammation through inhibiting signal molecules of ERK1/2 and NF-kB.