This cross-sectional study assessed the overall symptom burden, including the prevalence, frequency, severity, and distress of symptoms among hemodialysis patients, and explored the relationship between demographic characteristics, clinical variables, self-management, sense of coherence, social support, and symptom burden in these patients. Herein, a regression analysis was performed to determine associations with symptom burden. The mean score of symptom burden among the participants (n = 382) was 74.12, with an average number of 12 symptoms. The analysis revealed that self-management, sense of coherence, and social support were negatively associated with the overall symptom burden. The multiple regression model showed that 48.6% of the variance in symptom burden was explained by meaningfulness, emotional management, daily urine output, subjective support, gender, and manageability. These findings contribute to the knowledge of symptom burden among hemodialysis patients and some new predictors (self-management, sense of coherence, and social support) of their symptom burden.