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Herein, we investigated whether L-ascorbic acid and α-tocopherol supplementation has potential to alleviate arsenic induced immunotoxicities in thymus, spleen and circulating leukocytes. Forty-eight adult male Wistar rats were randomly divided into four groups before the treatments. Group-I (control); Group-II (sodium arsenite, 3mg/Kg/day/rat); Group-III [sodium arsenite + L-Ascorbic acid(L-AA) (200mg/Kg/day/rat) and α-tocopherol (α-T) (400mg/Kg/day/rat)]; Group-IV (L-AA and α-T). The result showed that sodium arsenite exposure (consecutive 30 days) caused weight reduction, structural alterations of thymus and spleen, accompanied by decrease in thymocyte and splenocyte counts. Decreased superoxide dismutase and catalase activities, increased malondialdehyde and protein-carbonyl contents, reduced Nrf2 and Bcl2 expression and increased p-ERK, NF-β, Bax, and cleaved-caspase-3 expression were also observed in thymus and spleen of arsenic exposed rat. Enhanced plasma ACTH and corticosterone, ROS induced apoptosis of lymphocytes were also observed. L-AA and α-T supplement has the potential to abrogate the deleterious impact of arsenic on thymus, spleen and circulating lymphocytes. Whole transcriptome analysis of leukocytes revealed that arsenic treatment augmented the expression of Itga4, Itgam, and MMP9 genes, which might help in transient migration of leukocytes through the endothelial cell layer. Supplementation with L-AA and α-T maintained Itga4, Itgam, and MMP9 gene expression within leukocytes at lower level.