To better understand the relationship between mindfulness and depression, we studied normal young adults (n = 27) who completed measures of dispositional mindfulness and depressive symptomatology, which were then correlated with (a) rest: resting neural activity during passive viewing of a fixation cross, relative to a simple goal-directed task (shape-matching); and (b) reactivity: neural reactivity during viewing of negative emotional faces, relative to the same shape-matching task. Dispositional mindfulness was negatively correlated with resting activity in self-referential processing areas, whereas depressive symptomatology was positively correlated with resting activity in similar areas. In addition, dispositional mindfulness was negatively correlated with resting activity in the amygdala, bilaterally, whereas depressive symptomatology was positively correlated with activity in the right amygdala. Similarly, when viewing emotional faces, amygdala reactivity was positively correlated with depressive symptomatology and negatively correlated with dispositional mindfulness, an effect that was largely attributable to differences in resting activity. These findings indicate that mindfulness is associated with intrinsic neural activity and that changes in resting amygdala activity could be a potential mechanism by which mindfulness-based depression treatments elicit therapeutic improvement.