Toxic heavy metal and metalloid (THMM) contamination poses a major global challenge, threatening human health and sustainable agriculture. The crucial role of the Cytochrome P450 (CYP) gene family in plant tolerance to THMMs has been recently highlighted, but there is still a lack of comprehensive understanding, especially in relation to metabolites. This study delved into the identification of CYP genes that are linked to the tolerance mechanisms of plants in response to heavy metal stress. The findings highlight the significant metabolic pathways that contribute to this resilience, using rice and Arabidopsis as exemplars. THMM exposure changed CYP gene expression in plants, and THMM antidotes mitigated its downregulation and that of flavonoid biosynthesis genes. CYP genes involved in THMM responses were predominantly enriched in the pathways associated with flavonoid synthesis, indicating functional adaptations to distinct stresses. Notably, anthocyanin (Ant) accumulation, a type of flavonoid, affected the uptake of various heavy metals in Brassica rapa, with flavonoid biosynthesis-associated genes correlating with Cd or As tolerance and Ant content. These findings highlight the critical importance of flavonoid metabolism and the intricate network of biosynthesis genes in bolstering plant resilience against heavy metal stress. This enhanced understanding paves the way for significant advancements in phytoremediation technologies, offering innovative solutions for soil and water decontamination.