Communication of cells among themselves and with other organelles is one of the crucial functions of connexins. It has been well-known for years that disease is associated with structural and functional alterations in connexin proteins. Connexin 43 is the highly expressed subtype amongst the rest of the connexins. There is emerging evidence that connexin 43 is critically necessary for physiological development. In this review, we examine the current understanding of connexin 43 across various systems, including the cardiovascular, nervous, and musculoskeletal systems, as well as its implications in retinal, dermatological, renal and cancer-related conditions, along with pleiotropic syndromes like oculodentodigital dysplasia. The discussion delves into the fundamental aspects of connexin structure and function while providing insight into the techniques utilized for their detection. Furthermore, we explored the effects of both the upregulation and downregulation of connexin 43, in addition to the phosphorylation of connexin 43 in the aforementioned disorders. Our understanding of connexin 43 biology can aid in diagnosing and treating multiple diseases.