Increasing anthropogenic activities related to industrialization and exposure to different toxicants increases the health hazards of industrial workers. Arsenic (As) exposure induces DNA damage and generates reactive oxygen species, which may result in many disease phenotypes. Present study explores the expression variation of As 3 methyltransferase (AS3MT) and superoxide dismutase (SOD2) genes in blood samples of industrial workers of different industries (brick kiln, paint, welding, pesticide, and furniture) using quantitative real-time polymerase chain reaction. A total of 250 blood samples of industrial workers were collected along with age- and gender-matched controls. Relative expression of AS3MT (p < 0.05) and SOD2 (p < 0.01) genes was found significantly downregulated in exposed workers compared to controls. Significant low levels of AS3MT and SOD2 gene expression were observed in workers in the paint and pesticide industry compared to other industries. Similarly, reduced expression of AS3MT (p < 0.05) and SOD2 (p < 0.01) was observed in smokers of industrial workers compared to smokers of the control group. Workers with >10 years of exposure had less AS3MT expression compared to workers with <10 years of exposure. Additionally, a positive Spearman correlation was observed between AS3MT versus SOD2 (r = 0.742; p < 0.0001) in industrial workers. This study suggests that decreased AS3MT and SOD2 expression levels may lead to bioaccumulation of As in the body accompanied by increased oxidative stress ultimately inducing DNA damage.