The aim of present study is to evaluate the association of oxidative stress with CYP1A2, CYP3A4, CYP2B6 and PON1 genetic variation in the pesticide exposed (occupationally) population. The present study demonstrated that the relative risk (RR) of declined antioxidant defense (Glutathione, Catalase, Superoxide Dismutase, Glutathione peroxidases, Glutathione Reductase) mechanism was significantly more in occupationally pesticide exposed group (n=120) as compared to unexposed group (n=84) from Bathinda district of Punjab (India). Although the age, BMI and alcohol intake were observed to be independent risk factors to decline the antioxidant defense mechanism, but the pesticide exposure was observed to be another risk factor to increase the oxidative stress inside the body. The gas chromatographic analysis revealed the residues of organophosphates (chlorpyriphos, dichlorvos, ethoprophos) and herbicides (atrazine, butachlor, alachlor, metolachlor) in the blood samples of population under investigation. Our results showed a dose dependent decrease in the cell viability following pesticide treatment (detected in blood samples) alone or in combination in hPBMC and A549 human lung cancer cell line. The pesticide treatment resulted the cell death in apoptotic manner via increased reactive oxygen species and cell cycle arrest at G0/G1 phase of cell cycle. Genetic variation analysis revealed the detection of two missense mutations [g.40991390G>T (SNP ID: rs33926104), g.40991388T>C (unknown)] on CYP2B6 gene of chromosome 19 in the coding region (exon 1) that results in the R29S and D28G amino acid change in CYP2B6 protein. One missense mutation (g.99758180C>T) has been detected in CYP3A4 gene that leads to change of amino acid from valine to isoleucine (V489I) at 489 location of protein. The mutated proteins have been predicted to change the structure and conformation of protein structure, thereby can alter its interaction with various DNA, membrane, ligand or . g.99757990A>T, g.99758050A>C and g.99758022A>T had been detected in CYP3A4 gene that may impair the post-translational modification of protein. So, the oxidative stress and pesticide residue accumulation inside the body could be the reason for more health problems in Bathinda district. Further, there is need to elaborate the research to study the genetic polymorphism in all pesticide metabolism genes.