Anxiety is prevalent among hospital inpatients and it has harmful effects on patient well-being and clinical outcomes. We aimed to characterize the sources of hospital distress and their relationship to anxiety. We conducted a cross-sectional study of inpatients (n = 271) throughout two Southeastern U.S. metropolitan hospitals. Participants completed a survey to identify which of 38 stressors they were experiencing. They also completed the State Trait Anxiety Inventory six-item scale. We evaluated the prevalence of stressors, their distribution, and crude association with anxiety. We then used multivariate logistic regression to estimate the association between stressors and clinically relevant anxiety, with and without adjusting for demographic variables. We used factor analysis to describe the interrelationships among stressors and to examine whether groups of stressors tend to be endorsed together. The following stressors were highly endorsed across all unit types: pain, being unable to sleep, feelings of frustration, being overwhelmed, and fear of the unknown. Stressors relating to isolation/meaninglessness and fear/frustration tend to be endorsed together. Stressors were more frequently endorsed by younger, female, and uninsured or Medicaid-insured patients and being female and uninsured was associated with anxiety in bivariate analysis. After controlling for the sources of distress in multivariate linear analysis, gender and insurance status no longer predicted anxiety. Feelings of isolation, lack of meaning, frustration, fear, or a loss of control were predictive. Study results suggest that multiple stressors are prevalent among hospital inpatients and relatively consistent across hospital unit and disease type. Interventions for anxiety or emotional/spiritual burden may be best targeted to stressors that are frequently endorsed or associated with anxiety, especially among young and female patients.