Fibroblast growth factor-21 (FGF-21) and Visfatin are associated with obesity. However; reviewing the literature; no studies were found to assess their role as potential markers for the metabolic disorders related to obesity in children. Assess the relations between serum FGF-21 and Visfatin with obesity and its metabolic disorders, and their use as potential predictors for metabolic risk factors in a sample of Egyptian obese children. This cross-sectional study included 111 Egyptian children (45 males and 66 females); aged 6–10 years to avoid the effect of puberty (prepubertal). The exclusion criteria (by full History taking and clinical examination) were the presence of any sign of puberty according to Tanner stage, the presence of identified causes of obesity (genetic syndromes, chromosomal or endocrinal disorders), chronic diseases (cardiovascular, gastrointestinal, and respiratory), or drug use like steroids; that would interfere with the type of obesity and affect the normal growth of the children. Also, any child with a BMI between 85 and 95th percentiles (overweight) was excluded from the study. All participating obese children were suffering from exogenous simple obesity. They were classified according to their body mass index (BMI) percentiles into 72 obese (BMI ≥ 95th), and 39 control non-obese ones (BMI > 15th to < 85th), based on the Egyptian Growth Charts for children and adolescents. Ethical approvals were granted from both the Ethics Committee of the “National Research Centre” and the “Faculty of Postgraduate Childhood Studies” (Approval No. 17/125). Also, informed written consent was taken from either of the parents and assent from the participating children. They were subjected to blood pressure assessment, anthropometric measurements (weight [Wt], height [Ht], BMI, waist [WC], and hip [HC] circumferences), and laboratory evaluation (Visfatin, FGF-21, LDL, HDL, TG, cholesterol, fasting glucose, insulin, and calculation of HOMA-IR). Mann–Whitney test and Spearman’s correlation test were applied. Obese children had significantly higher values than control ones regarding all the studied clinical (SBP, DBP), anthropometric parameters (Wt, Ht, BMI, WC, and HC), FBG, Insulin, HOMA-IR, Visfatin, and FGF-21, and had significantly lower values regarding HDL and Cholesterol. Among obese children, both FGF-21 and Visfatin had significant negative correlations with BMI and HC. At the same time, serum FGF-21 had a highly significant positive correlation with HDL. Visfatin and FGF-21 had highly significant positive correlations with each other. In the control group, both serum Visfatin or FGF-21 had insignificant correlations with each other and with all the studied clinical and anthropometric parameters. FGF-21 and Visfatin are related to the obesity markers, but they cannot be used as potential predictors for metabolic disturbance in obese prepubertal children; both had insignificant correlations with the metabolic risk factors.