Background: The development of major depressive disorder in patients at end of life often goes undiagnosed, as it is difficult to distinguish from preparatory grief and/or hypoactive delirium in this unique patient population. If this preliminary barrier of appropriate diagnosis is overcome, it can be quite difficult to properly select and adjust pharmacological therapy. Many well-established antidepressants take four to five weeks for maximal effectiveness (which may be far too long of a titration period for patients at end of life), have various contraindications to patients' comorbid chronic conditions (particularly patients with cardiovascular disease), or may simply be ineffective. Case: We present a case report of severe treatment-resistant depression in an end-stage heart failure patient enrolled in hospice care. Discussion: We discuss the potential use of a single low-dose intravenous racemic ketamine infusion to reduce end-of-life suffering related to depression, despite the theoretical contraindication of ketamine use in such patients, in part, due to its sympathomimetic secondary effect.