Perceived stress (PS), which reflects the tendency to appraise one’s life situations as stressful and overwhelmed, is a stable predictor for depression. Here, we used resting-state functional magnetic resonance imaging to investigate the neural basis of PS and the underlying brain mechanism linking PS and depression in 217 adolescents. We found that PS was positively related to the spontaneous activity in the left superior frontal gyrus (SFG). Furthermore, PS mediated the link between the left SFG activity and depression. Altogether, our study might present a neurofunctional marker of PS and reveal an underlying brain-stress mechanism for predicting depression.