Patients with serious illness and short prognoses often experience depression and suicidal ideation. Traditional antidepressants are limited by delayed onset, creating a need for rapidly acting therapies. In this Palliative Care Rounds, we examine the evidence for ketamine/esketamine's efficacy as antidepressants, including evidence specific to people with serious illnesses. In psychiatric studies, intravenous ketamine produces rapid (1-24 hours), moderate-to-large antidepressant effects lasting 1-2 weeks, with a number needed to treat of 3 in the first week. Esketamine nasal spray demonstrates similar early efficacy and is United States Food and Drug Administration-approved for treatment-resistant depression and major depression with suicidal ideation. Evidence in serious illness is limited to several peri-operative cancer trials and small open-label studies, which show short-term reductions in depressive symptoms and suicidal ideation but do not address long-term management or maintenance dosing. Safety across serious illness studies is generally favorable, with transient dissociation, hypertension, and somnolence the most common adverse effects; serious adverse events remain rare. Ketamine and esketamine offer the strongest evidence among rapid-acting antidepressants and may be preferred when urgent symptom relief is needed. However, rigorous psychiatric trials in serious illness are lacking. Clinicians should consider prognosis, access to Risk Evaluation and Mitigation Strategies-certified esketamine programs or equivalent regulatory frameworks outside the US, and the need for an appropriate maintenance regimen when integrating ketamine into palliative care depression management.