Drug-induced cardio-hepatic toxicity is the foremost cause of heart and liver damage, with the use of antimicrobial-agent. Most patients, although recuperate after discontinuing the offending-agent, severe cases may consequence in progressive disease. Azithromycin is a rare cause of idiosyncratic drug-induced cardiac and liver injury. This semi-synthetic macrolide has a substantial potency against both gram-positive and gram-negative organisms due to the presence of a nitrogen atom in its ring. A search was performed in PubMed, Scopus, Google Scholar and Research Gate. Azithromycin divulges a lower number of interactions with proteins, whereas, QTc prolongation with torsades de pointes (Tdp) and polymorphic ventricular tachycardia are communally occurred in cardiovascular system, due to dysregulation of intracellular [Ca++] via the Na+-Ca++ exchanger activity, leading to delayed after depolarizations. In addition azithromycin-induced liver injury was more cholestatic in nature, with an ALT/ALP ratio of <2 ULN, contributing vanishing bile duct syndrome. This review hereafter revealed the adverse effect of azithromycin in relation with cardio – hepatic toxicity.