Palliative care is frequently part of nursing practice in acute care settings. Research has evaluated nurses’ general perceptions on end-of-life care in hospital and identified symptom management as a concern. The aim of this study was to explore nurses’ perceptions regarding end-of-life medication use in an acute care setting to enable identification of variables that may impact symptom management and medication use at the end of life. Using a qualitative description methodology, 22 nurses from 8 medical and surgical units participated in 7 focus groups. Nurses were less likely to use medication when having difficulty identifying symptoms and when medications were not familiar. Other factors included conflicting perspectives and the emotional experience. Nurses felt that physicians were often reluctant to involve the palliative care team and experienced delays in obtaining orders or clarifying goals of care. Nurses felt uncomfortable with medication use when their feelings conflicted with family perspectives and found communication with families challenging overall. Nurses expressed a desire to achieve comfort but felt fears surrounding medication use. Fears included hastening death, adverse effects such as depressed respirations, and the possibility of pain pump errors or inappropriate use. Education and resources regarding symptom assessment and common end-of-life medications were identified as important.