Appropriate interpretation of pleasurable, rewarding experiences favors decisions that enhance survival. Conversely, dysfunctional affective brain processing can lead to life-threatening risk behaviors (e.g., addiction) and emotion imbalance (e.g., mood disorders). The state of sleep deprivation continues to be associated with maladaptive emotional regulation, leading to exaggerated neural and behavioral reactivity to negative, aversive experiences. However, such detrimental consequences are paradoxically aligned with the perplexing antidepressant benefit of sleep deprivation, elevating mood in a proportion of patients with major depression. Nevertheless, it remains unknown how sleep loss alters the dynamics of brain and behavioral reactivity to rewarding, positive emotional experiences. Using functional magnetic resonance imaging (fMRI), here we demonstrate that sleep deprivation amplifies reactivity throughout human mesolimbic reward brain networks in response to pleasure-evoking stimuli. In addition, this amplified reactivity was associated with enhanced connectivity in early primary visual processing pathways and extended limbic regions, yet with a reduction in coupling with medial frontal and orbitofrontal regions. These neural changes were accompanied by a biased increase in the number of emotional stimuli judged as pleasant in the sleep-deprived group, the extent of which exclusively correlated with activity in mesolimbic regions. Together, these data support a view that sleep deprivation not only is associated with enhanced reactivity toward negative stimuli, but imposes a bidirectional nature of affective imbalance, associated with amplified reward-relevant reactivity toward pleasure-evoking stimuli also. Such findings may offer a neural foundation on which to consider interactions between sleep loss and emotional reactivity in a variety of clinical mood disorders.