Background: Obesity in childhood and adolescence has reached epidemic proportions in recent decades. Methods: In the present study, we determined the concentrations of apelin-12, vaspin and resistin in 106 children and adolescents with overweight or obesity before and after the implementation of a multidisciplinary, personalized lifestyle intervention program of diet, sleep and exercise for 1 year. All subjects attended our Center for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence. Results: Following the lifestyle intervention, there were significant decreases in BMI (p < 0.01), apelin-12 (p < 0.05) and resistin (p < 0.01) concentrations, and an increase in vaspin (p < 0.01) concentration. Glucose was the best positive predictor of apelin-12 (b = 0.236, p < 0.05), and osteopontin was the best negative predictor of changes in apelin-12 (b = −0.299, p < 0.05). Vaspin correlated positively with adiponectin (b = 0.29, p < 0.05), while vitamin D (b = 0.621, p < 0.05) was the best positive predictor of vaspin. BMI z score (b = −0.794, p < 0.05), HDL (b = −0.284, p < 0.05) and HbA1C (b = −0.262, p < 0.05) were the best negative predictors of changes in vaspin. BMI z score was the best positive predictor of resistin (b = 0.437, p < 0.05). Conclusions: These findings suggest that apelin-12, vaspin and resistin correlate with indices of obesity, glucose, lipids and bone metabolism, while interaction with other proteins, such as osteopontin and adiponectin, was also noted. Therefore, apelin-12, vaspin and resistin may be used as biomarkers in children and adolescents with overweight and obesity.