Introduction: Management of acutely poisoned patients presents a persistent challenge in critical care, particularly in cases involving polypharmacy, and mixed-drug overdose. Establishing standardized protocols for managing polypharmacy and unknown overdose in intensive care units (ICU), where practices differ significantly across institutions, deems necessary. This review aims to consolidate current understanding of epidemiology, diagnostic methods, toxidrome recognition, and the careful application of antidotal and extracorporeal therapies in managing polypharmacy and unidentified drug overdoses in intensive care settings.

Methods: A literature search was conducted on PubMed, Scopus, and Web of Science from January 2000 to September 2025. A qualitative synthesis of data was utilized to develop a practical framework that incorporates bedside assessment, toxidrome identification, and evidence-based therapeutic interventions. The emphasis was placed on the importance of empirical treatment and advanced organ support modalities. Results: Rapid identification of toxidromes is crucial in situations where the specific agents are unknown. This is complemented by targeted antidotal therapy informed by clinical evaluation and toxicology consultation, as well as extracorporeal therapies such as hemodialysis, hemoadsorption, continuous renal replacement therapy, or extracorporeal membrane oxygenation (ECMO) when necessary. Extracorporeal elimination techniques are utilized exclusively in severe or difficult-to-treat cases.

Conclusion: Structured diagnostic and therapeutic algorithms facilitate timely escalation, coordination among multiple disciplines, and decisions grounded in evidence. Future advancements in biomarkers, and artificial intelligence have the potential to enhance diagnostic accuracy, and treatment efficacy. Simultaneously, public health initiatives and preventive strategies remain crucial for reducing poisoning incidents and alleviating the strain on ICUs.