Introduction: Childhood obesity is a significant and growing problem worldwide. Recent evidence suggests Follistatin-like 1 (FSTL1) and family with sequence similarity to 19 member A5 (FAM19A5) to be novel adipokines. However, very few studies have examined the plasma levels of FSTL1 and FAM19A5 in children. Therefore, this cross-sectional study evaluated the association between serum FSTL1 and FAM19A5 levels with obesity in children and investigated the relationship between FSTL1 and FAM19A5 and glucose metabolism or endothelial injury. Methods: Fifty-five obese children and 48 healthy controls were recruited. Plasma FSTL1 and FAM19A5 levels were detected using ELISA. In addition, the association between the clinical data and anthropometric parameters was analyzed. Results: Serum FAM19A5 levels were significantly decreased in the obese children, at 189.39 ± 19.10 pg/mL, compared with those without obesity, at 211.08 ± 38.09 pg/mL. Serum concentrations of FSTL1 were also significantly lower in the obese children, at 0.64 (0.37–0.64) ng/mL, compared with those without obesity, at 1.35 (1.05–2.12) ng/mL. In addition, FAM19A5 (OR = 0.943; P = 0.003) was a predictor of insulin resistance in obese children compared with healthy controls. Lastly, serum FAM19A5 and FSTL1 played mediating roles in insulin resistance in children. Conclusion: The serum levels of FAM19A5 and FSTL1 were decreased in obese children; therefore, FAM19A5 and FSTL1 likely play important roles in glucose metabolism in obese children.