Background: Critically ill patients routinely experience profound physiological derangements that significantly alter drug pharmacokinetics and pharmacodynamics. While fluid shifts and organ dysfunction are classically implicated, the gut microbiome has recently emerged as a critical driver of unpredictable drug absorption, giving rise to the field of pharmacomicrobiomics. Objective: This narrative review aims to comprehensively evaluate the mechanisms through which the dysbiotic gut microbiome in critical care settings hijacks the pharmacokinetics of enterally administered drugs.