Abstract Obesity is a worldwide multifactorial disease caused by an imbalance in energy metabolism, increasing adiposity, weight gain, and promoting related diseases such as diabetes, cardiovascular diseases, neurodegeneration, and cancer. Recent findings have reported that metabolic stress related to obesity induces a mitochondrial stress response called mitochondrial unfolded protein response (UPR mt ), a quality control pathway that occurs in a nuclear DNA–mitochondria crosstalk, causing transduction of chaperones and proteases under stress conditions. The duality of UPR mt signaling, with both beneficial and detrimental effects, acts in different contexts depending on the tissue, cell type, and physiological states, affecting the mitochondrial function and efficiency and the metabolism homeostasis during obesity, which remains not fully clarified. Therefore, this review discusses the most recent findings regarding UPR mt signaling during obesity, bringing an overview of UPR mt across different metabolic tissues.