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(1) Background: Previous studies suggest that exposure to nitrogen dioxide (NO2) has a negative impact on health. But few studies have explored the association between NO2 and blood lipids or fasting plasma glucose (FPG), as well as gene–air pollution interactions. This study aims to fill this knowledge gap based on a pedigree cohort in southern China. (2) Methods: Employing a pedigree-based design, 1563 individuals from 452 families participated in this study. Serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), and FPG were measured. We investigated the associations between short-term NO2 exposure and lipid profiles or FPG using linear mixed regression models. The genotype–environment interaction (GenoXE) for each trait was estimated using variance component models. (3) Results: NO2 was inversely associated with HDLC but directly associated with TG and FPG. The results showed that each 1 μg/m3 increase in NO2 on day lag0 corresponded to a 1.926% (95%CI: 1.428–2.421%) decrease in HDLC and a 1.400% (95%CI: 0.341–2.470%) increase in FPG. Moreover, we observed a significant genotype–NO2 interaction with HDLC and FPG. (4) Conclusion: This study highlighted the association between NO2 exposure and blood lipid profiles or FPG. Additionally, our investigation suggested the presence of genotype–NO2 interactions in HDLC and FPG, indicating potential loci-specific interaction effects. These findings have the potential to inform and enhance the interpretation of studies that are focused on specific gene–environment interactions.