General ward nurses play a key role in discharge planning for end-stage cancer patients. It is necessary to assess the factors regarding their practice to promote discharge planning in accordance with end-stage cancer patients’ wishes. This study aimed to investigate the relationships between general ward nurses’ practice of discharge planning for end-stage cancer patients, self-efficacy, ethical behavior, attitude, knowledge and experience, perceived skills, and perceived barriers. A total of 288 general ward nurses from nine hospitals in a city in Japan completed the questionnaire. Path analysis was conducted to test the hypotheses. The results showed that nurses’ self-efficacy, ethical behavior (do-no-harm, do-good), knowledge (experience of attending home care seminars), and perceived skills (assertiveness) were positively and directly related to the practice of discharge planning. Nursing experience and perceived skills (assertiveness) were positively associated with discharge planning practice, while perceived barriers (death discussion) and attitude (degree of leaving it to discharge planning nurses (DPNs)) were negatively associated, with self-efficacy acting as a mediator. Thus, our findings show that it is important to enhance self-efficacy and nursing ethical behavior to improve the practice of discharge planning. Accordingly, education regarding home care, assertive communication skills, death discussion, and ethics is needed for general ward nurses.