Emotion Regulation Flexibility (ERF) is defined as an individual's ability to adaptively respond to changing situations and goals. Deficits in the adaptiveness of ERF have been linked to depression, suggesting a critical relationship between emotional processing and mental health. The objective of the present study was to investigate how variations in situational and goal-related contexts influence the association between ERF adaptiveness and depression. We employed functional magnetic resonance imaging (fMRI) and behavioral tasks to explore this relationship. Participants completed tasks designed to provoke changing situations and changing goals, while fMRI captured neural activity. Our findings revealed a significant negative correlation between depression scores and ERF adaptiveness. Specifically, during changing-situations, activation was observed in temporal and limbic regions, while changing-goals engaged prefrontal and parietal regions. Correlation analyses indicated that the adaptiveness of ERF was supported by distinct neural contributions: the temporoparietal junction (TPJ) in the changing-situations condition and the dorsolateral prefrontal cortex (dlPFC) in the changing-goals condition. Furthermore, the functional coupling between the dlPFC and the ventromedial prefrontal cortex (vmPFC) mediated the relationship between ERF adaptiveness and depression during changing-goals, but not during changing-situations. These findings elucidate the neural mechanisms of ERF adaptiveness and its implications for understanding and addressing depression.