Drug-induced organ toxicity/injury, especially in the liver, kidney, and gastrointestinal tract, is a systematic disorder that causes oxidative stress formation and inflammation resulting in cell death and organ failure. Current therapies target reactive oxygen species (ROS) scavenging and inhibit inflammatory factors in organ injury to restore the functions and temporary relief. Organ cell function and tissue homeostasis are maintained through gap junction intercellular communication, regulating connexin hemichannels. Mis-regulation of such connexin, especially connexin (Cx) 43, affects a comprehensive process, including cell differentiation, inflammation, and cell death. Aim to describe knowledge about the importance of connexin role and insights therapeutic targeting. Cx43 misregulation has been implicated in recent decades in various diseases. Moreover, in recent years there is increasing evidence that Cx43 is involved in the toxicity process, including hepatic, renal, and gastrointestinal disorders. Cx43 has the potential to initiate the immune system to cause cell death, which has been activated in the acceleration of apoptosis, necroptosis, and autophagy signaling pathway. So far, therapies targeting Cx43 have been under inspection and are subjected to clinical trial phases. This review elucidates the role of Cx43 in drug-induced vital organ injury, and recent reports compromise its function in the major signaling pathways.