Background: Depression is a comorbid disabling problem and potentially affects patient likelihood of survival. The aims of this study were to recognize the characteristics of depression and investigate associated predictor factors in patients with oral cancers. Methods: A cross-sectional and correlational design was used to collect data for this study conducted in northern Taiwan. A set of questionnaires was used to measure depression, symptom distress, performance status, social support, and demographic and disease-related information. Logistic regression was conducted to determine important factors predicting depression. Results: A total of 132 oral cancer patients participated in this study. Of these, 18.2% were identified as depression cases. The patient average performance status score was 90 or higher. Patients reported mild-to-moderate levels of symptom distress. The majority of social support was from families. Religious belief, alcohol use, symptom distress, and social support from family were found to be important factors predicting depression. Patients with religious belief with alcohol use reported greater symptom distress, and those with lower levels of social support from families were significantly more likely to develop depression. Conclusions: Clinicians should assess patient emotional status and manage symptoms in a timely manner to enhance coping abilities. Supportive care provides assurance during the acute survivor phase.