This review systematically elucidates the detailed molecular mechanisms, particularly the roles of the Nrf2/HO-1, PI3K/Akt, and NF-κB pathways, clarifying how genistein exerts its antioxidant, anti-inflammatory, and anti-apoptotic effects in five common diseases (PD, AD, DM, CVD, and cancer) that are prevalent in the population. Here, NFE2L2 is linked to cancer.