Objective This study aims to explore the effect of propofol deep sedation on brain activity by observing changes in amplitude of low‑frequency fluctuations (ALFF) during this state. Methods This was a prospective, observational study involving healthy volunteers aged 18 to 60 years. Subjects underwent target‑controlled infusion of propofol while fully awake, and their sedation status was assessed using the modified Observer's Assessment of Alertness/Sedation Scale. Resting‑state functional magnetic resonance imaging (rs‑fMRI) scans were performed in both awake and deep sedation states to analyze changes in mean ALFF (mALFF). Results A total of 26 healthy volunteers were included in the study. The average effect site concentration for achieving deep sedation with propofol was (2.35±0.49) mg/L. Compared with the awake state, mALFF increased in the bilateral temporal lobes, parts of the frontal lobes, and occipital regions during deep sedation (all P<0.05), while mALFF decreased in the bilateral frontal lobes, the middle frontal gyrus, and parts of the occipital regions (all P<0.05). The difference in the number of voxels between regions with increased mALFF and those with decreased mALFF was not statistically significant (P>0.05). Conclusions During deep sedation with propofol, neuronal activity is enhanced in the bilateral temporal lobes, parts of the frontal lobes, and occipital regions, while it is reduced in the bilateral frontal lobes, the middle frontal gyrus, and parts of the occipital regions. These findings suggest that the sedative mechanism of propofol may involve combined effect of enhancement in some brain regions and suppression in others.