Obesity is frequently accompanied by metabolic dysfunction and micronutrient imbalances, including iron. Despite the critical role of iron in metabolic regulation, the tissue-specific effects of iron dysregulation remain unclear. In this study, we used leptin-deficient ob/ob mice to investigate whether iron homeostasis is altered during obesity progression and contributes to organ-specific metabolic adaptations. We measured serum metabolites, tissue iron and relative expression levels of proteins involved in iron homeostasis and key metabolic pathways across multiple organs of ob/ob mice at 3 and 5 months of age (3OB and 5OB), and their respective lean controls (3LC and 5LC). Multivariate analysis revealed that changes in hepatic proteins related to glycemic control and ferritin levels were key factors distinguishing obese mice from lean controls, regardless of age. In contrast, mitochondrial proteins and ferritin in adipose and hippocampal tissues better explained the variance between 3OB and 5OB groups, suggesting that the adipose tissue and hippocampus undergo continuous remodeling during obesity progression. Tissue iron and ferritin levels showed moderate to strong correlations with several key metabolic enzymes, especially with mitochondrial proteins. In linear regressions between tissue ferritin and either cytochrome c oxidase or ATP synthase, these two mitochondrial proteins exhibited opposite angular coefficients across all evaluated tissues. Additionally, 3OB and 5OB mice displayed opposite patterns in adipose tissue and hippocampus, indicating that these proteins play key roles in time- and tissue-specific metabolic adaptation during obesity progression. These findings suggest that local iron dynamics can contribute to metabolic dysfunction in obesity and consequent comorbidities.