The current study elucidates the uncharacterized biohazard associated with rice growth in arsenic and fluoride co-contaminated sites. Analysis of the arsenic-tolerant rice cultivar, Muktashri (known to restrict arsenic uptake) revealed that fluoride largely stimulated arsenic bioaccumulation in the stressed tissues and vice versa. Gene expression studies revealed that high arsenic uptake was facilitated by the fluoride-dependent up regulation of phosphate transporter2 (PT2), PT8 and low silicon rice1 (Lsi1), and elevated fluoride accumulation was stimulated by the arsenic-mediated induction of chloride channels (CLCs). The endogenous accumulation of fluoride and arsenic increased reactive oxygen species (ROS), O, membrane peroxidation and arsenic localization within tissues. This inhibited plant growth by triggering chlorosis, electrolyte leakage, malondialdehyde production (due to high lipoxygenase activity), protein carbonylation, protease activity and methylglyoxal accumulation due to inhibited glyoxylase activity. Metabolic analysis showed inhibited proline biosynthesis along with increased channelization of glutathione towards phytochelatin synthase and glutathione-S-tranferase-dependent pathways. Inhibition of the antioxidant enzymes like catalase, ascorbate peroxidase and guaiacol peroxidase validated the inefficient scavenging of HO during combined stress. In silico analyses predicted the ecotoxicological risks of arsenic-fluoride complex formed during joint stress. Overall, our investigation illustrated the underlying mechanism of arsenic-fluoride co-uptake which resulted in complete suppression of the 'tolerant'-phenotype in Muktashri seedlings.