Psychological resilience reflects the capacity to bounce back from stress, which plays an important role in health and well-being. However, less is known about the neural substrate for psychological resilience and the underlying mechanism for how psychological resilience enhances subjective well-being in the healthy brain. To investigate these issues, we employed fractional amplitude of low-frequency fluctuations (fALFF) measured with resting-state fMRI in 100 young healthy adults. The correlation analysis found that higher psychological resilience was related to lower fALFF in the left orbitofrontal cortex (OFC), which is involved in reward-related processing and emotion regulation. Furthermore, the mediation analysis indicated that psychological resilience acted as a full mediator of the association between the fALFF in left OFC and subjective well-being indicators (i.e. life satisfaction and hedonic balance). Importantly, these results remained significant after controlling for the effect of gray matter volume and regional homogeneity in the region. Overall, the present study provides the further evidence for functional neural substrates of psychological resilience and reveals a potential mechanism that psychological resilience mediates the effect of spontaneous brain activity on subjective well-being.