This study aimed to investigate the effect of comprehensive education and care (CEC) program on anxiety, depression, quality of life, and survival in patients with hepatocellular carcinoma (HCC) who underwent surgical resection. Totally 136 patients with HCC who underwent hepatectomy were randomly assigned to CEC group and control group as 1:1 ratio. CEC group received health education, psychological nursing, caring activity, and telephone condolence, whereas control group received basic health education and rehabilitation for 12 months. Anxiety and depression were assessed by Hospital Anxiety and Depression Scale (HADS); quality of life was evaluated using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). HADS-Anxiety (HADS-A) score was decreased at 9 month (M9) and M12, and reduction in HADS-A score (M12-M0) was greater in CEC group compared with control group. At M12, percentage of anxiety patients was less, but anxiety severity was similar in CEC group compared with control group. HADS-Depression (HADS-D) score was decreased at M12, and reduction in HADS-D score (M12-M0) was greater in CEC group compared with control group. At M12, percentage of depression patients were less but depression severity was similar in CEC group compared with control group. In addition, QLQ-C30 global health status and functional score was increased at M12, and score improvement (M12-M0) was greater in CEC group compared with control group. In addition, overall survival was longer in CEC group compared with control group. CEC relieves anxiety and depression, improves quality of life, and prolongs survival in patients with HCC underwent surgical resection.