Background: Gut hormones change with weight loss in adults but are not well studied in obese youth. Objective: The primary aim was to evaluate how gut hormones and subjective appetite measure change with dietary weight loss in obese adolescents. Methods: Participants were a subset of those taking part in the ‘Eat Smart Study’. They were aged 10–17 years with body mass index (BMI) > 90th centile and were randomized to one of three groups: wait-listed control, structured reduced carbohydrate or structured low-fat dietary intervention for 12 weeks. Outcomes were fasting glucose, insulin, leptin, adiponectin, total amylin, acylated ghrelin, active glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide (GIP), pancreatic polypeptide (PP) and total peptide tyrosine-tyrosine. Pre- and postprandial subjective sensations of appetite were assessed using visual analogue scales. Results: Of 87 ‘Eat Smart’ participants, 74 participated in this sub-study. The mean (standard deviation) BMI z-score was 2.1 (0.4) in the intervention groups at week 12 compared with 2.2 (0.4) in the control group. Fasting insulin (P = 0.05) and leptin (P = 0.03) levels decreased, while adiponectin levels increased (P = 0.05) in the intervention groups compared with control. The intervention groups were not significantly different from each other. A decrease in BMI z-score at week 12 was associated with decreased fasting insulin (P < 0.001), homeostatic model of assessment-insulin resistance (P < 0.001), leptin (P < 0.001), total amylin (P = 0.03), GIP (P = 0.01), PP (P = 0.02) and increased adiponectin (P < 0.001). There was no significant difference in appetite sensations. Conclusions: Modest weight loss in obese adolescents leads to changes in some adipokines and gut hormones that may favour weight regain.