Although mitigating burnout has long been a pressing issue in healthcare, recent global disasters, including the COVID-19 pandemic and wars, have exacerbated this problem. Medical professionals are frequently exposed to diverse job-induced distress; furthermore, the importance of people’s sense of coherence (SOC) over work has been addressed to better deal with burnout. However, the neural mechanisms underlying SOC in medical professionals are not sufficiently investigated. In this study, the intrinsic fractional amplitude of low-frequency fluctuations (fALFF) were measured as an indicator of regional brain spontaneous activity using resting-state functional magnetic resonance imaging in registered nurses. The associations between participants’ SOC levels and the fALFF values within brain regions were subsequently explored. The SOC scale scores were positively correlated with fALFF values in the right superior frontal gyrus (SFG) and the left inferior parietal lobule. Furthermore, the SOC levels of the participants mediated the link between their fALFF values in the right SFG and the depersonalization dimension of burnout. The results deepened the understanding of the counter role of SOC on burnout in medical professionals and may provide practical insights for developing efficient interventions.