Oxidative stress may act as a contributing factor in the development of an elevated body mass index (BMI). Oxidative stress has the potential to modulate genetic activity at various levels, including gene transcription and protein function regulation. Nevertheless, the interplay between genetic variants and oxidative stress in relation to BMI remains to be elucidated. Based on this premise, we studied the potential association between 723 single-nucleotide polymorphisms (SNPs) located within a set of 212 genes and both BMI and oxidative stress parameters in 1502 adults from the general Spanish population (Hortega Study). Oxidative stress parameters measured included malondialdehyde (MDA) levels, 8-oxo-2'-deoxyguanosine (8-oxo-dG) levels and oxidised/reduced glutathione ratio (GSSG/GSH). We also examined the potential impact of the interaction between these SNPs and oxidative stress levels on BMI. The genes selected regulate several key biological processes, including obesity, blood pressure, inflammation, lipid metabolism and redox homeostasis. Our findings indicate a robust association between specific genes and both BMI and oxidative stress parameters. Significant BMI-related interactions between genes and oxidative stress parameters were identified, which have a multifactorial impact on oxidative stress modulation and on BMI. SNPs identified in genes such as NPPA, CPT1A, DDIT3, NOX and IL6ST were significantly associated with all oxidative stress parameters analysed, indicating a substantial influence on BMI modulation. The results provide compelling evidence of a significant relationship between oxidative stress levels and genetic background. Our data provide new insights into BMI modulation by oxidative stress levels, highlighting a role for TNF as a key player in the interrelation of oxidative stress and BMI.