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Alprazolam (commercially known as Xanax®) remains one of the most frequently prescribed benzodiazepines across the globe. Since its introduction in 1976, it has been widely used for treating anxiety-related conditions and panic disorders. Typical therapeutic regimens range up to 4 mg per day for generalized anxiety, while higher doses, often between 6–9 mg per day, are used in managing panic and phobic disorders. Due to its fast absorption, quick onset of action, and relatively short duration, alprazolam also carries a notable risk for misuse, particularly for its sedative and mood-enhancing effects. Misuse frequently occurs alongside other substances such as alcohol, opioids (including methadone and oxycodone), and stimulants like cocaine. To develop a consolidated source of scientific information on this drug, an extensive search of major scientific databases—including PubMed, Medline, and ScienceDirect— was conducted. The findings are organized into a comprehensive overview designed to support forensic toxicologists in evaluating alprazolam findings in both ante-mortem and post-mortem samples. Key topics include concentration ranges reported in positive forensic cases, with attention given to factors such as post-mortem redistribution, drug stability, and interactions with co-ingested substances. Additionally, the review outlines the pharmacological profile of alprazolam and discusses current analytical techniques used for its detection in biological matrices.