In this study, we investigated the prevalence of mental health problems among patients with cancer and whether oncology nurse navigation improved their mental health outcomes and medical experience. In this randomized controlled clinical trial, we recruited 128 outpatients with cancer via purposive sampling from a teaching hospital in northern Taiwan. Participants were randomly assigned to the navigation group ( = 61) or the usual care group ( = 67). Data were collected from January 2019 to July 2020 using questionnaires, including the self-reported Distress Thermometer, Hospital Anxiety and Depression Scale, Demoralization Scale, and Patient Assessment of Chronic Illness Care. Data were collected at baseline and after three and six months of the intervention. Descriptive and analytical statistical analyses were performed. The prevalence rates of anxiety, depression, distress, and demoralization were 17.9%, 15.7%, 29.7%, and 29.7%, respectively. After three months, the participants in the navigation group exhibited significantly reduced levels of anxiety, demoralization, and emotional distress (reduced by 92%, 75%, and 58%, respectively) and reported a better medical experience (odds ratio = 1.40) than those in the usual care group.