Despite enormous development in the field of drug development, cancer still remains elusive. Compromised immunity stands as a roadblock to the successful pharmacological execution of anti-cancer drugs used clinically currently. Recently some breakthrough cancer treatment strategy like nano-formulation, extracellular vesicles treatment, natural antioxidant therapy, targeted immunotherapy, gene therapy, thermal ablation and magnetic hyperthermia, and pathomics and radiomics has been developed and tested pre-clinically as well as clinically. However, clinical efficacy of such therapies is yet to establish and some are too costly to be utilized by patients from poor and developing countries. At this juncture, researchers are heading towards the search of medicines from natural sources that is higher safety margin and multitarget pharmacological efficacy compared to conventional treatments. Mushroom is used traditionally as food as well as drug since time immemorial due to its immunomodulatory effect which is loaded with proteins, low fat content and cholesterol. Mushrooms are recommended as one of the best vegetarian diets for immunosuppressed cancer and HIV/AIDS patients. Mushrooms are well-known for their anti-cancer activity that impacts hematopoietic stem cells, lymphocytes, macrophages, T cells, dendritic cells (DCs), and natural killer (NK) cells in the immune system. This comprehensive review article emphasizes on the molecular mechanisms of cancer genesis, conventional anti-cancer therapy as well as reported some significant breakthrough in anti-cancer drug development, anti-cancer activity of some selected species of mushrooms and their bioactive phytoconstituents followed by a brief discussion of recent anti-cancer efficacy of some metallic nanoparticles loaded with mushrooms.