Converging evidence supports neuroimmune factors in depression psychopathology. We previously reported reduced depression-like behavior in immunomodulatory G-protein-coupled receptor, T cell death-associated gene-8 (TDAG8) deficient mice. Here, we expand on those findings by investigating depression- and anxiety-associated behaviors, and cytokine profiles in TDAG8-deficient mice. TDAG8-deficiency reduced depression- and anxiety-associated behaviors in the forced swim test (FST), open-field test and elevated zero maze. Interestingly, cytokine expression, particularly IL-6, was attenuated within hippocampus and spleen in TDAG8-deficient mice following the FST. There were no differences in immune-cell frequencies. Collectively, these data suggest a contributory role of TDAG8 in neuroimmune regulation and depression-associated physiology. •TDAG8-deficient mice show attenuated depression-like and anxiety-like behavior.•TDAG8−/− mice had attenuated post-stress interleukin-6 (IL-6) in hippocampus.•Reduced basal IL-6 expression in spleen was observed in TDAG8−/− mice.•TDAG8 receptor regulates neuroimmune homeostasis and depression-associated behaviors.