Purpose <p>This study aimed to determine serum levels of aquaporin-7 (AQP7), adiponectin (ADPN), and tumor necrosis factor-alpha (TNF-α) and to investigate their associations with metabolic parameters in children with obesity.</p> Methods <p>This study included 60 healthy control children (Group 1), 39 overweight/obese (Group 2), and 60 morbidly obese (Group 3) children aged 5–18 years. Serum AQP7, ADPN, and TNF-α levels were measured using enzyme-linked immunosorbent assay (ELISA). Insulin resistance (IR) was assessed using the homeostatic model assessment of insulin resistance (HOMA-IR).</p> Results <p>ADPN and AQP7 levels were significantly lower in Group 2 compared with Group 1, however a partial increase was observed in Group 3 (<i>p</i> &lt; 0.001). TNF-α levels did not differ significantly among the groups (<i>p</i> = 0.532). Metabolic parameters including body mass index (BMI), HOMA-IR, homeostasis model assessment of beta-cell function (HOMA-β), glycated hemoglobin (HbA1c), and lipid profile progressively deteriorated with increasing obesity severity (<i>p</i> &lt; 0.05 to <i>p</i> &lt; 0.0001). Cardiovascular risk indices were significantly higher in Group 2 and Group 3 (<i>p</i> &lt; 0.001).</p> Conclusion <p>Childhood obesity is associated with significant alterations in AQP7 and ADPN levels, which vary according to obesity severity. Compensatory mechanisms might emerge in morbid obesity, consistent with the partial increase in these biomarkers. The progressive worsening of metabolic parameters and cardiovascular risk indices with increasing BMI highlights the importance of early intervention. AQP7 and ADPN, alongside conventional metabolic markers, may serve as useful indicators of obesity-related metabolic dysfunction in children.</p>