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Oxidative stress and antioxidants play an important role in obesity etiopathology. Genetic variants, including single nucleotide polymorphisms (SNPs) of the antioxidant-related genes, may impact disease risk in several populations. This preliminary study aimed to explore the association of 12 SNPs related to superoxide dismutase (<i>SOD</i>), catalase (<i>CAT</i>), glutathione peroxidase (<i>GPX</i>), glutathione-S-transferase (<i>GST</i>), and nitric oxide synthase (<i>NOS</i>) genes with obesity susceptibility in a Saudi population. A total of 384 unrelated participants, including 154 (40.1%) obese individuals, were enrolled. TaqMan OpenArray Genotyping assays were used. Six SNPs were significantly more prevalent in obese cohorts: (1) <i>GSTM1</i> rs1056806*C/T; (2) <i>SOD1</i> rs2234694*A; (3) <i>SOD2</i> rs4880*G; (4) <i>SOD3</i> rs2536512*A; (5) <i>GPX1</i> rs1800668*A; (6) <i>NOS3</i> rs1799983*G. Four SNPs were associated with higher obesity risk under heterozygote and dominant models for <i>GSTM1</i> rs1056806 (C/T), homozygote model for <i>SOD2</i> rs4880 (A/G), and homozygote and recessive models for <i>GPX1</i> rs1800668 (A/G). In contrast, <i>SOD3</i> rs2536512 (A/G) were less likely to be obese under heterozygote and dominant models. The CGAG, CAAA, TGGG, and CGAG combined genotypes showed a higher risk of obesity. In conclusion, the present results suggest that oxidative-stress-related genetic determinants could significantly associate with obesity risk in the study population.