<jats:sec><jats:title>Background</jats:title><jats:p>The immune system has major roles in the brain and related psychopathology. Disrupted interleukin-6 secretion and aberrant amygdala emotional reactivity are well-documented in stress-related mental disorders. The amygdala regulates psychosocial stress-related interleukin-6 affected by related genes. These led us to comprehensively examine the relationship between interleukin-6, amygdala activity, and stress-related mental symptoms under gene-stressor interactions.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>One hundred eight nonclinical participants with various levels of anxiety/depression underwent magnetic resonance imaging scans during an emotional face task for amygdala activity and saliva collection (at 10-time points across 2 days) for the total output and diurnal patterns of interleukin-6. Gene-stressor interactions between rs1800796 (C/G) and rs2228145 (C/A) and stressful life events for the biobehavioral measures were explored.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The blunting of interleukin-6 diurnal pattern was associated with hypoactivation of the basolateral amygdala in response to fearful (vs. neutral) faces (<jats:italic>t</jats:italic> = 3.67, FWE-corrected <jats:italic>p</jats:italic> = 0.003), and was predominantly observed in individuals with rs1800796 C-allele homozygotes and negative life changes in the past year (<jats:italic>F</jats:italic> = 19.71, <jats:italic>p</jats:italic> &lt; 0.001). When considered in a comprehensive model, the diminished diurnal pattern predicted greater depressive symptoms (<jats:italic>β</jats:italic> = −0.40), modulated by the amygdala hypoactivity (<jats:italic>β</jats:italic> = 0.36) and rs1800796-stressor interactions (<jats:italic>β</jats:italic> = −0.41; all <jats:italic>p</jats:italic> &lt; 0.001).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Here we show that the blunted interleukin-6 diurnal rhythm predicts depressive symptoms, modulated by amygdala emotional hyporeactivity and gene-stressor interactions. These findings indicate a potential mechanism underlying vulnerability to depressive disorders, suggesting their early detection, prevention, and treatment through the understanding of immune system dysregulation.</jats:p></jats:sec>