While amyloid precursor protein (APP) overexpression in adipose tissue is a recognized consequence of high-fat diet (HFD) feeding, its role in metabolically active organs and the mechanisms linking it to systematic dysfunction remain unclear. In particular, the potential for diet-induced APP dysregulation in the other tissues and the contribution of its βC-terminal fragment (βCTF) are poorly characterized. Using a high-fat diet (HFD) mouse model to induce systematic metabolic stress, we assessed APP and βCTF levels across multiple tissues. HFD triggered a tissue-specific response, with APP levels increasing >2-fold in visceral and subcutaneous white adipose tissue (WAT) and in the kidney but remained unchanged in the liver and brain. βCTF levels were significantly elevated in the visceral WAT (3-fold) and kidney. In these responsive tissues, APP and βCTF accumulated within mitochondria, which coincided with significantly reduced complex I and IV activities. Complementary in vitro studies confirmed that APP levels can dictate mitochondrial function. Furthermore, we identified that cytokines–IL-4, IL-13, TNF-α, and IL-1β–induced APP transcription, providing a mechanistic link between diet-induced inflammation and APP dysregulation. Collectively, our findings demonstrate that APP is overexpressed in response to HFD in select peripheral tissues, which coincides with reduced mitochondrial complex enzyme activities and increased cytokine levels.