Diminished QoL is a major concern among older adults in Alzheimer’s disease associated neurodegenerative processes, such as amnestic MCI. To better assess and improve their well-being, it is important to understand the neural basis of QoL and factors leading to better QoL. In this case-controlled study (MCI, n = 18; healthy control (HC), n = 21), we examined the relationship between QoL and cognition-demanding acute stress tasks, and the neural mechanism linking these two. Acute stress tasks were the total 20-minute Stroop Word Color task and Dual 1-back task. The discrepancy of amplitude of low-frequency fluctuations (ALFF) of the resting-state functional magnetic resonance imaging administered before and after the tasks was extracted as the neural stress reactivity. The discrepancy of psychological valence and arousal rating was considered the psychological stress reactivity. QoL and ALFF reactivity in three regions (anterior cingulate cortex, medial prefrontal cortex (MPFC), and superior frontal gyrus (SFG)) significantly differed between groups. The associations of MPFC and SFG’s reactivity with QoL were not group-specific while the associations of valence and arousal reactivity with QoL were group-specific. Greater arousal reactivity (adaptive coping) was associated with better QoL in HC; lower valence reactivity (maladaptive coping) was associated with worse QoL in MCI. SFG reactivity significantly mediated the association between valence reactivity and QoL for the entire sample. The MCI group may be more sensitive to maladaptive coping. Enhancing SFG, especially among those with MCI, may be a way to intervene in the negative impact of maladaptive stress regulation on QoL.