The aim of this study was to decipher the reprogramming of protective machineries and sulfur metabolism, as responses to time-dependent effect of fluoride stress for 10 and 20days in two indica rice (Oryza sativa ) varieties. Unregulated accumulation of fluoride via chloride channels (CLC1 and CLC2) in 10-day-old (cv. Khitish) and 20-day-old (cv. MTU1010) seedlings caused higher accumulation of H2 O2 and superoxide anion that eventually incited chlorophyll loss and electrolyte leakage, along with the formation of malondialdehyde and methylglyoxal. Higher fluoride accumulation also enhanced lipoxygenase and NADPH oxidase activities, which further aggravated the oxidative damages. However, for stressed 20-day-old Khitish and 10day-old MTU1010 seedlings, plant growth was maintained with lesser oxidative damages due to upregulated expression of H+ -ATPase and FEX along with the elevated level of cysteine and H2 S, which could be linked with higher activity of ATP-S, OASTL, and DES. The activity of the enzymatic antioxidants (superoxide dismutase, catalase, ascorbate peroxidase, guaiacol peroxidase, and glutathione peroxidase) and level of non-enzymatic antioxidants (anthocyanins and flavonoids) were also enhanced that strengthened the antioxidative potential of the seedlings. Our work demonstrated that differential reprogramming of the protective metabolites and sulfur assimilation pathways is responsible for the differential pattern of adaptive strategies against fluoride stress in the two indica rice varieties, with Khitish exhibiting tolerance against long-term fluoride stress, whilst MTU1010 showing high susceptibility to the same.