Chronic pain is one of the highest costs in clinical therapy, often appearing comorbid with depression. They present with overlapping clinical conditions and common pathological pathways especially in neuroinflammation, both of which can be reversed by electroacupuncture (EA). Transient receptor potential V1 receptor (TRPV1) is a Ca[Formula: see text] permeable ion channel that responds to brain inflammation and has a known role in the development of chronic pain and depression. Here, we investigate the role of TRPV1 and its related molecules in a mouse model of inflammation-induced chronic pain and depression using Complete Freund’s adjuvant (CFA). We measured inflammatory mediators in plasma and evaluated the TRPV1 signaling pathway in the medial prefrontal cortex (mPFC), hypothalamus, and periaqueductal gray (PAG) of the mouse brain. Mechanical and thermal hyperalgesia as well as depressive-like behaviors were induced using the open field test and forced swimming test. Therapeutic effects were observed in EA and [Formula: see text] mice in measures of chronic pain and depression. Inflammatory mediators induced by CFA injection were attenuated by EA and deletion. TRPV1 and downstream molecules were significantly decreased in the mPFC, hypothalamus, and PAG of mice, effects which were reversed by EA and knockout. We provide novel evidence that these inflammatory mediators modulate the TRPV1 signaling pathway and suggest new potential therapeutic targets for chronic pain and depression.