Objective The incidence of multiple primary cancers (MPCs) is increasing, but little is known about psychological distress in this population. The purpose of this study is to review and synthesize the literature regarding what is known about psychological distress in adults who have experienced MPC diagnoses. Methods All potentially eligible studies identified in PubMed and CINAHL were reviewed by 2 independent evaluators, and each relevant article was assessed for methodological quality. Data were extracted, organized, and recorded using a coding log, PRISMA flow diagram, and a standardized table of evidence. Effect size (ES) values were calculated using Cohen's d. Results Five of the 562 potentially relevant articles were selected for final analysis. MPC survivors, when compared with single cancer survivors, had lower global quality of life (d = 0.32–0.37), poorer emotional role function and stress (d = 0.08–0.20), greater and more frequent distress (d = 0.11–0.37), and greater subclinical anxiety (d = 0.15). Depressive symptoms were variable (d = 0.01–0.22), and no differences between MPC and single cancer groups were identified for sleep and suicidal ideation. Conclusion There is a substantial lack of evidence focused on psychological distress among the growing MPC survivor population. ES noted in the 5 studies reflect small but potentially significant increases in psychological distress in survivors of MPC compared with survivors of a single cancer. Clinicians should be aware of this at‐risk population when screening for distress in cancer survivors. Suggestions for future research are provided.