Background <p>Parental obesity has been identified as one of the most important early risk factors for childhood obesity, but molecular mechanisms driving this greater predisposition remain to be elucidated.</p> Methods <p>In this study, we recruited a cohort comprising children with obesity (body mass index over two <i>z</i>-scores above the age/sex-adjusted mean of the Spanish reference population, age range: 6–12&#xa0;years), born to parents with obesity (<i>N</i> = 18) or without obesity (<i>N</i> = 41), as well as matched healthy controls (<i>N</i> = 26). Plasma and erythrocyte samples were collected for comprehensive biochemical and metabolomics analyses, this latter by applying high-throughput liquid chromatography–mass spectrometry. Then, a combination of multivariate and univariate statistical tools was applied to unravel the molecular pathogenic impairments that parental obesity may imprint in the offspring.</p> Results <p>Interestingly, we found parental obesity to be associated with exacerbated unhealthy metabolic outcomes in the offspring with obesity, as mirrored in higher fasting insulin levels (<i>p</i> = 2.8 × 10⁻⁸) and HOMA-IR scores (<i>p</i> = 1.3 × 10⁻⁸). This was in turn accompanied by altered concentrations in 87 plasma and 51 erythroid metabolites (<i>p</i> &lt; 0.05) involved in a variety of obesity-related pathways that are known to be tightly regulated by insulin action, namely energy-related metabolism, branched-chain amino acids, nitrogen homeostasis, redox systems, and steroid synthesis (i.e., steroid hormones, bile acids). Additional analyses demonstrated that most metabolomics associations were largely attenuated after adjusting for the HOMA-IR scores.</p> Conclusions <p>Therefore, we hypothesize that insulin resistance could be a major driving force in mediating deleterious programming mechanisms induced by parental obesity in the offspring.</p>