Gray’s Reinforcement Sensitivity Theory (RST) predicts that the Behavioral Inhibition System (BIS) may relate to coping-motivated problem gambling, given its central role in anxiety. Studies examining the BIS-problem gambling association, however, are mixed. The revised RST posits that the Behavioral Approach System (BAS) may moderate the effect of the BIS on coping-motivated problem gambling. A concurrently strong BAS may highlight the negatively reinforcing effects of gambling, which may strengthen coping motives and increase gambling-related harms. We examined these interactive effects to clarify the moderators and mediators of the negative reinforcement pathway to problem gambling. Data came from a larger investigation of problem gambling among individuals with mood disorders. All participants (N = 275) met criteria for a lifetime depressive or bipolar disorder. During a two-day assessment, participants completed a diagnostic assessment and self-reports. Mediated moderation path analysis showed positive indirect effects from the BIS to problem gambling via coping motives at high, but not at low, levels of BAS-Reward Responsiveness and BAS-Fun Seeking. Enhancement motives were also found to mediate the associations of BAS-Fun Seeking and BAS-Drive with problem gambling. Reward Responsiveness and Fun Seeking facets of the BAS may strengthen coping gambling motives within the mood disorders.