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Simple Summary: Patients with advanced cancer frequently seek care in the emergency department and usually present with a constellation of symptoms. In an emergency/urgent setting, it is crucial to understand the severity of these symptoms, which include pain, fatigue, nausea, disturbed sleeping, and distress, as these can greatly influence patient outcomes and the care of cancer patients. In this study, we aimed to explore the relationship between the severity of these symptoms, the diagnosis of delirium, and short-term survival outcomes. Understanding this relationship offers important insights that aid in managing these symptoms, improving patient outcomes, and enhancing a patient's overall quality of life. Background/Objectives: Patients with advanced cancer often present to the emergency department (ED) with pain and distressing symptoms that are not systematically evaluated. The current study investigated the association of symptom severity with the diagnosis of delirium and short-term survival. Methods: In this secondary analysis of a prospective randomized study of delirium among advanced cancer patients in the ED, in which symptoms were assessed by the MD Anderson Symptom Inventory (MDASI), we analyzed the distribution of MDASI item scores by 90-day mortality (Kolmogorov–Smirnov), the association of MDASI item scores with short-term mortality (logistic regression models), and the symptoms in those with or without delirium (Mann–Whitney U test or chi-square test). Results: Of the 243 patients included, 222 (91.4%) had complete MDASI scores. The MDASI median symptom scores for pain, fatigue, and interference with work were the highest. A significant difference in MDASI item score distribution with 90-day mortality was observed for fatigue (p = 0.018), shortness of breath (p < 0.001), difficulty remembering (p = 0.038), lack of appetite (p = 0.035), drowsiness (p < 0.001), feeling sad (p = 0.031), and interference with walking (p < 0.001). In multivariable logistic regression models, shortness of breath (adjusted OR 1.15, 95% CI 1.04–1.26, p = 0.005) and drowsiness (adjusted OR 1.17, 95% CI 1.05–1.33, p = 0.008) were associated with 90-day mortality, adjusting for age, race, performance status, and cancer type. The median total MDASI score was significantly higher in patients with delirium than in those without (88, IQR 83–118 vs. 80, IQR 55–104; p < 0.001). Conclusions: Patients with advanced cancer presenting to the ED had severe symptoms, some of which were associated with shorter survival. These findings underscore the necessity of systematic symptom assessment, focusing on shortness of breath, drowsiness, fatigue, difficulty remembering, lack of appetite, feeling sad, and feeling distressed, to enhance clinical decision-making and improve the care of patients with advanced cancer. Additional longitudinal studies are needed to evaluate the improvement in symptoms and quality of life for these patients. [ABSTRACT FROM AUTHOR]