Ferroptosis is an inflammatory programmed cell death process that is dependent on iron deposition and lipid peroxidation. The P2X7 receptor not only is involved in the pain process but also is closely related to the onset of depression. Gallic acid (3,4,5-trihydroxybenzoic acid), which is naturally found in a variety of plants, exhibits anti-inflammatory, antioxidant, and analgesic effects. This study established a rat model with the comorbidity of chronic constrictive injury (CCI) plus chronic unpredictable mild stress (CUMS) to explore the role and mechanism of gallic acid in the treatment of pain and depression comorbidity. Our experimental results showed that pain and depression-like behaviors were more obvious in the chronic constriction injury (CCI) plus chronic unpredictable mild stimulation (CUMS) group than they were in the sham operation group, and the P2X7-reactive oxygen species (ROS) signaling pathway was activated. The tissue iron concentration was increased, and mitochondrial damage was observed in the CCI plus CUMS group. These results were alleviated with gallic acid treatment. Therefore, we speculate that gallic acid inhibits the ferroptosis of the spinal microglia by regulating the P2X7-ROS signaling pathway and relieves the behavioral changes in rats with comorbid pain and depression.