Polypharmacy is increasingly common among older and multimorbid patients and represents one of the most frequent yet underrecognized challenges in internal medicine. Although traditionally defined as the concurrent use of five or more medications, its clinical relevance extends beyond the number of prescribed drugs. The risk emerges from the complex interaction between medications, comorbidities, organ dysfunction, frailty, acute illness, and changing therapeutic goals. In acute care settings, clinical deterioration is often attributed to disease progression, while the cumulative therapeutic burden may remain overlooked. This narrative clinical review aims to reframe polypharmacy as a hidden and potentially modifiable contributor to acute clinical deterioration in internal medicine. Particular attention is given to drug–drug and drug–disease interactions, renal impairment, hemodynamic vulnerability, electrolyte disturbances, bleeding risk, delirium, falls, and prescribing cascades. High-risk clinical phenotypes include patients with chronic kidney disease, heart failure, atrial fibrillation, diabetes, frailty, anemia, and acute infection. The review also emphasizes medication reconciliation, renal dose adjustment, structured prescribing tools such as STOPP/START and Beers Criteria and deprescribing as essential components of clinical reasoning. Polypharmacy should not be approached merely as a numerical threshold or a pharmacological problem, but as a dynamic clinical syndrome with diagnostic and therapeutic implications. Before escalating treatment or attributing deterioration solely to underlying disease, internists should ask whether treatment itself has become the trigger.