Acetazolamide is the commonly prescribed oral and intravenous carbonic anhydrase inhibitor; over the years, its use in clinical practice has decreased in favor of more recent drugs. However, it is a rather handy drug, which can be useful in several clinical settings when managing critically ill patients. The objective of this review is the evaluation of the most recent evidence on the use of acetazolamide in emergency medicine and critical care medicine. Furthermore, the safety profile of this drug has been evaluated. This is a narrative review on the use of acetazolamide in the main contexts in which this drug can be useful in emergency situations for patients with potential critical issues. For the timeline 1999-2024, a search was conducted on the main scientific platforms; resources of greatest relevance for the use of acetazolamide in critical care and emergency medicine were selected. The most common emergency situations in which a critically ill patient could benefit from acetazolamide therapy are acute heart failure, acute mountain sickness, post hypercapnic metabolic alkalosis, idiopathic intracranial hypertension and acute angle-closure glaucoma. In a few cases, however, randomized controlled clinical trials have been conducted. There are also other less solid indications based mostly on experience or retrospective data. Acetazolamide seems to be an overall safe drug; serious side effects are rare and can be avoided by carefully selecting the patients to be treated. Acetazolamide represents a precious resource for emergency physicians and intensivists; critical patients with different conditions can in fact benefit from it; furthermore, acetazolamide is a safe drug if administered to correctly selected patients.