Purpose <p>According to the meaning-making model, distress arises from discrepancies between individuals’ global meaning and situational meaning. This study aimed to advance understanding cancer survivors’ meaning appraisals by examining associations between global belief and goal violations and well-being, while testing whether religious and spiritual factors—often highly relevant to individuals diagnosed with cancer—might modify these relationships.</p> Methods <p>For this cross-sectional study, 306 Christian cancer survivors were surveyed online on their religion, cancer diagnosis, belief and goal violations, distress, fear of cancer recurrence, Christian flourishing, and posttraumatic stress from cancer. Sequential regression analysis was used to examine effects of belief and goal violations, religiousness/spirituality, and their interaction on distress, fear of cancer recurrence, Christian flourishing, and posttraumatic stress from cancer.</p> Results <p>In final regression models inclusive of covariates, variables and interaction terms, meaning violations were associated with wellbeing. Specifically, extrinsic goal violations predicted greater fear of recurrence and flourishing. Intrinsic goal violations predicted greater general distress, fear of recurrence, and posttraumatic stress from cancer. Belief violations predicted greater fear of recurrence and posttraumatic stress from cancer. Both intimacy with God and theodical struggle significantly interacted with meaning violations to predict wellbeing, but effects were inconsistent across outcomes in terms of buffering or exacerbating effects.</p> Conclusion <p>Christian cancer survivors’ perceptions of cancer as violating their meaning systems—both their beliefs and goals—has important implications for their adjustment and may serve as intervention targets. Further, religiousness/spirituality may play a complex role, buffering some effects of perceiving violations but also exacerbating others.</p>