Andrographolide, the main bioactive component separated from Andrographis paniculata in 1951, has been scrutinized with a modern drug discovery approach for anti-inflammatory properties since 1984. Identification of new uses of existing drugs can be facilitated by searching for evidence linking them to known or yet undiscovered drug targets and human disease states to develop new therapeutic indications.Furthermore, a wide spectrum of biological properties of andrographolide such as anticancer, antibacterial, antiviral, hepatoprotective, antioxidant, anti-malarial, anti-atherosclerosis are also reported. However, poor water solubility and instability limit its clinical application. It becomes crucial to enhance its pharmacological function and find a new treatment option for more diseases. Therefore, this article reviews the major recent developments in andrographolide, including repurposing applications in different diseases and underlying mechanisms, particularly focusing on pharmacological enhancement of andrographolide such as derivatives, chemical modifications with potent biological activity and drug delivery. The repurposing and pharmacological enhancement of andrographolide would not only have exciting therapeutic potential to different diseases to facilitate drug marketing, but also decrease the economic burden on healthcare worldwide.