Objective: The need to understand potential precipitants of smoking relapse is exemplified by relapse rates as high as 95%. The Self-Control Strength model, which proposes that self-control is dependent upon limited resources and susceptible to fatigue, may offer insight into relapse processes. The current study tested the hypothesis that self-control depletion (SCD), produced from engagement in emotional suppression, would serve as a novel antecedent for cessation failure, as indexed by a validated laboratory analogue of smoking lapse and relapse. We also examined whether SCD effects interacted with those of a well-established relapse precipitant (i.e., nicotine deprivation). Craving and behavioral economic indices (delay discounting and demand) were tested as hypothesized mechanisms for increased cessation failure. Ultimately, a moderated mediation model was used to test nicotine deprivation as a hypothesized moderator of SCD effects. Method: We used a 2 × 2 (12-hr deprivation vs. no deprivation; SCD vs. no SCD) factorial between-subjects design (N = 128 smokers). Results: The primary hypothesis of the study was supported, as SCD increased lapse behavior (p = .04). Nicotine deprivation significantly increased craving, cigarette demand, delay discounting, and lapse behavior. No main effects were found for SCD on putative mediators (i.e., craving, demand, and discounting), but the SCD and deprivation manipulations interacted upon craving (p = .04). The moderated mediation model was significant. SCD was found to increase craving among nicotine deprived smokers, which mediated effects on lapse behavior. Conclusions: SCD appears to play an important role in smoking relapse and may be a viable target for intervention.