Exposure to metal(loid)s during critical developmental windows could result in permanent damage to the target organ system, increasing susceptibility to disease later in life. In view of the fact that metals(loid)s have been shown to work as obesogens, the aim of the present case-control study was to evaluate the modification effect of exposure to metal(loid)s on the association between SNPs in genes involved in metal(loid) detoxification and excess body weight among children. A total of 134 Spanish children aged 6–12 years old were included (88 controls and 46 cases). Seven SNPs (GSTP1 rs1695 and rs1138272; GCLM rs3789453, ATP7B rs1061472, rs732774 and rs1801243; and ABCC2 rs1885301) were genotyped on GSA microchips, and ten metal(loid)s were analysed in urine samples through Inductively coupled plasma mass spectrometry (ICP-MS). Multivariable logistic regressions were conducted to assess the genetic and metal exposures' main association and interaction effects. GSTP1 rs1695 and ATP7B rs1061472 showed significant effects on excess weight increase in those children carrying two copies of the risk G allele and being highly exposed to chromium (ORa = 5.38, p = 0.042, p interaction = 0.028 for rs1695; and ORa = 4.20, p = 0.035, p interaction = 0.012 for rs1061472) and lead (ORa = 7.18, p = 0.027, p interaction = 0.031 for rs1695, and ORa = 3.42, p = 0.062, p interaction = 0.010 for rs1061472). Conversely, GCLM rs3789453 and ATP7B rs1801243 appeared to play a protective role against excess weight in those exposed to copper (ORa = 0.20, p = 0.025, p interaction = 0.074 for rs3789453) and lead (ORa = 0.22, p = 0.092, p interaction = 0.089 for rs1801243). Our findings provide the first proof that interaction effects could exist between genetic variants within GSH and metal transporting systems and exposure to metal(loid)s, on excess body weight among Spanish children. Display omitted •GSTP1 rs1695 and ATP7B rs1061472 contributed to excess weight in the presence of chromium and lead.•GCLM rs3789453 and ATP7B rs1801243 showed the opposite effect for copper and lead exposures.•First gene – metal(loid) interactions reported in excess body weight among children.