Natural product andrographolide isolated from the plant Andrographis paniculata shows a plethora of biological activities, including anti-tumor, anti-bacterial, anti-inflammation, anti-virus, anti-fibrosis, anti-obesity, immunomodulatory and hypoglycemic activities. Based on extensive chemical structural modifications, a series of andrographolide derivatives with improved bioavailability and druggability has been developed. Moreover, greater understanding of their mechanisms of action at the molecular and cellular level has been thoroughly investigated. In this review, we give an outlook for the therapeutical potential of andrographolide and its derivatives in diverse diseases and highlighted the drug design, pharmacokinetic and mechanistic studies for the past ten years, together with a brief overview of the pharmacological effects. Notably, we focused to provide a critical enlightenment of the area of andrographolide and its derivatives with the intent of indicating the future perspectives, challenges and limitations. We believe that this review paper will benefit drug discovery where andrographolide was used as a template, shed light on the identification of drug targets for andrographolide and its analogs, as well as increase our knowledge for using them for therapeutic application, including the treatment for various forms of cancers.