PhytochemicalsPhytochemicals are natural bioactive compounds in plants, exhibiting diverse physiological activities that can impact human health. Our understanding of bioactive phytochemicals’ nutritional and therapeutic benefits has expanded in recent years. Over the past three decades, isothiocyanatesisothiocyanatesITC (ITCsITC), a group of naturally occurring phytochemicals, have garnered extensive attention for their potential therapeutic benefits. ITCsITC are formed through the hydrolytic action of a heat-labile enzyme, myrosinasemyrosinase (EC 3.2.3.1; beta-thioglucosidase), on glucosinolatesglucosinolatesGS (GS) within plants. GS and ITCsITC have also emerged with remarkable antioxidant properties and a significant role in disease remediation. Although derived from various sources, all ITCs are recognized as activators of nuclear factor-erythroid 2-related factor 2 (Nrf2), a master regulator of cellular defense mechanisms. However, extensive research has demonstrated that ITCs can simultaneously initiate multiple cellular signaling events beyond the Nrf2/Keap1 pathway. Enhancing our current understanding of the role of oxidative stress and free radicals produced by cellular processes has emphasized the potential of various antioxidant enzymes targeted by ITCsITC in therapeutic interventions against challenging diseases. This chapter explores the intricate mechanisms by which ITCsITC regulate endogenous antioxidants by neutralizing harmful free radicals, mitigating oxidative stress, and their profound impact on a spectrum of disease remediation.