AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase critical in regulating cellular metabolism in response to intracellular energy levels. The activation of AMPK is subject to intracellular energy demand, and once activated, it maintains intracellular energy levels under stress conditions. While the role of AMPK was thought to primarily address endocrine metabolic disorders, such as type 2 diabetes, numerous reports have highlighted the involvement of AMPK in various molecular pathways associated with the growth and development of cancer. There have been substantial reports suggesting AMPK as a possible tumor suppressor. Research involving AMPK in cancer growth and development has created an interesting approach in recent years as a target for chemotherapy. The involvement of AMPK signaling in protein synthesis, cell cycle, cell growth, and proliferation, as well as autophagy, is through the metabolic regulations implicating p53, eEF2K, and P13K/Akt/mTOR signaling pathways. There is growing interest toward investigating AMPK modulators as potential candidates for cancer treatment. Consequently, the ability of AMPK activators to influence various molecular pathways through AMPK activation could be beneficial for cancer patients, with the potential to minimize undesired side effects. Here, we highlight ample evidence supporting AMPK as a target for cancer research and focus exclusively on various treatment strategies that involve the activation of multiple downstream targets of AMPK for an efficient therapeutic strategy.