In spite of the progress in treatment strategies, cancer remains a major cause of death worldwide. Therefore, the main challenge should be the early diagnosis of cancer and the design of an optimal therapeutic strategy to increase the patient’s life expectancy as well as the continuation of the search for increasingly active and selective molecules for the treatment of different forms of cancer. In the recent decades, research in the field of natural compounds has increasingly shifted towards advanced and molecular level understandings, thus leading to the development of potent anti-cancer agents. Among them is the diterpene lactone andrographolide, isolated fromAndrographis paniculata(Burm.f.) Wall. ex Nees that showed shows a plethora of biological activities, including not only anti-cancer activity, but also anti-inflammatory, anti-viral, anti-bacterial, neuroprotective, hepatoprotective, hypoglycemic, and immunomodulatory properties. Andrographolide has been shown to act as an anti-tumor drug by affecting specific molecular targets that play a part in the development and progression of several cancer types including breast, lung, colon, renal, and cervical cancer, as well as leukemia and hepatocarcinoma. This review comprehensively and systematically summarized the current research on the potential anti-cancer properties of andrographolide highlighting its mechanisms of action, pharmacokinetics, and potential side effects and discussing the future perspectives, challenges, and limitations of use.