Although much emphasis has been placed on the impact of ambiguity on cognitive processes, the impact of mental health disorder symptoms and racial/ethnic disparities in cancer perception of fatalism and ambiguity remains less explored. This study explored the association between mental health disorder symptoms and negative cancer perceptions. Also, we assessed differences in these outcomes within mental health disorder symptoms and racial/ethnic subgroups to investigate the association between cancer perceptions and the other covariates within the aforementioned subgroups. We used the 2019–2020 Health Information National Trends Survey data (N = 9,303) to assess the perception of cancer fatalism and cancer communication ambiguity and employed weighted multivariable logistic regression to determine the effects of mental health disorder symptoms using the Patient Health Questionnaire-4 (PHQ-4) scale on these negative cancer perceptions among United States adults. People with moderate [Adjusted Odds Ratio (AOR) = 1.58, 95