<p>Parenteral therapies are vital in critical care, oncology, and nutrition, offering rapid onset, precise dosing, and high bioavailability. However, their safety is often compromised by admixture incompatibilities and drug-device interactions that threaten stability, efficacy, and patient outcomes. This review synthesizes the current scientific understanding of physicochemical and material-based incompatibilities in reconstituted formulations, intravenous drug admixtures, and parenteral nutrition, highlighting their implications for safety and efficacy. Key risks include precipitation, pH shifts, phase separation, leachables, particulates, and adsorption, with documented links to treatment failure, infusion reactions, and product recalls. Interactions with packaging systems-glass, plastics, elastomers, and siliconized components-are critically examined, alongside regulatory requirements for extractables, leachables, and container–closure integrity. Emerging strategies, such as advanced packaging materials, fluoropolymer-coated elastomers, and real-time monitoring technologies, are highlighted as pathways to safer parenteral therapy. By uniting clinical insights with regulatory requirements and emerging technologies, this review highlights admixture compatibility studies as essential to ensuring the safety, efficacy, and reliability of parenteral drug delivery.</p> Graphical Abstract <p></p>