Although the effects of cognitive reappraisal in regulating negative emotion are generally well documented, its regulatory effects are usually not very strong because the ordinary reappraisals employed in previous studies were insufficient to overcome the mental set or response bias toward negative situations. In this study, we developed a new strategy employing creative reappraisals that provides an insightful reinterpretation of the negative stimulus. We believe this approach, through adopting a guided (creative) reappraisal rather than self-generation strategy, will greatly improve the emotion regulation effect of reappraisal through activating the neural networks representing the process of deep and structural mental representational change accompanied by the feeling of positive emotion and mental reward. The behavioral results suggested that 1) regarding the transient regulatory effect, creative reappraisal resulted in a positive rating for standardized negative pictures; 2) creative reappraisal had a long-lasting effect in reducing negative affect. In parallel with these behavioral results, the imaging data indicated that 1) creative reappraisal was specifically associated with greater engagement of the amygdala and hippocampus as well as regions in the ventral striatum, and 2) the engagement of the amygdala predicted the transient regulatory effect of creative reappraisal, while the involvement of the hippocampus and the ventral striatum predicted long-term regulatory effects. These findings suggest that the superior regulatory effect of creative reappraisal could be mediated by amygdala-based salient emotional arousal, hippocampus-based new association formation, and striatum-based mental rewarding to lead to a novel and positive experience that could be kept in long-term memory. This research indicates the key role of creative insight in reappraisal and presents a novel and highly efficient reappraisal strategy.