BACKGROUND: Depression is often accompanied by high levels of smoking behavior, and smoking can act as a risk factor for depression. However, there is limited neuroimaging evidence regarding the association between depression and smoking, especially the impact of this association on the brain stability remains unclear. Therefore, this study aimed to assess the interaction effect between smoking and depression from a neurodynamic perspective. METHOD: We assessed the resting-state functional magnetic resonance imaging from 193 participants (55 depressed smokers
51 depressed non-smokers
25 healthy smokers
62 healthy non-smokers) and calculated 3 regional activity dynamic indicators, including dynamic regional homogeneity (dReHo), dynamic amplitude of low-frequency fluctuations (dALFF), and dynamic fractional ALFF (dfALFF). Principal component analysis was conducted on these 3 dynamic indicators, and the first component was extracted for the subsequent 2 × 2 factor designs statistical analysis. RESULT: We observed the interaction between smoking and depression increases the instability of regional activity in the precentral gyrus and precuneus. Compared with HCs, patients with depression showed increased instability of regional activity across widespread regions such as the precentral gyrus, thalamus, and medial frontal gyrus. No main effects of smoking were observed. In depressed smokers, the instability of regional activity in left precuneus is positively correlated with anxiety symptoms. CONCLUSIONS: Our findings indicate that smoking potentially exacerbates brain abnormal instability in depression, implying a clinical need to require patients with depression to abstain from smoking.