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Therapeutic drug failure poses a significant global health burden, particularly in developing regions with high environmental toxicant exposure. While traditionally attributed to factors such as substandard drugs, genetic polymorphisms, and non-compliance, emerging evidence implicates heavy metals as under-recognized modulators of drug efficacy. This systematic review assessed how heavy metals potentially interfere with the pharmacokinetics and pharmacodynamics of drugs. Following PRISMA guidelines, peer-reviewed articles published between 1999 and 2024 were retrieved from PubMed, ScienceDirect, Web of Science, Scopus and Google Scholar. Studies investigating in vivo, in vitro or clinical evidence of heavy metal interference with therapeutic drug action were eligible. Out of 139 studies identified, 20 studies met the inclusion criteria. Cadmium, lead and mercury were the most implicated metals. Approximately 60% of studies demonstrated that oxidative stress could induce loss of therapeutic drug efficacy, while 40% showed enzyme inhibition (notably CYP3A4 and CYP2C9) or transporter impairment. Experimental models linked these effects to anti-hypertensives, antidiabetics, and drugs used in the management of metabolic disorders. Environmental heavy metal exposures may hinder therapeutic responses through oxidative and metabolic disruption. Integrating environmental exposure assessment into global pharmacovigilance and clinical pharmacology could enhance drug response predictability and treatment success.