As the core hub of energy metabolism of eukaryotes, mitochondria participate in a variety of cellular activities, such as metabolic regulation of cell matrix, apoptosis, activation of signal transduction pathways and other key life activities., and their status is closely related to the initiation and progression of various diseases. Neurodegenerative diseases are mainly characterized by progressive loss and dysfunction of neurons, and in this process mitochondrial dysfunction is considered one of the important triggers. The specific mechanisms by which mitochondrial dysfunction leads to neurodegenerative diseases have received widespread attention. When misfolded or unfolded proteins was detected, a reaction called mitochondrial unfolded protein response (mtUPR) is activated to ensure that the protein folds properly or degrades to restore mitochondrial function. As a stress defense mechanism in mitochondria, mtUPR mainly regulates the expression of nuclear coding genes, such as chaperones and proteases, and thus alleviate mitochondrial stress. Studies have found that, in addition to the misfolded and unfolded protein, other mitochondrial stresses, such as abnormalities in mitochondrial DNA and reactive oxygen species (ROS), can also induce mtUPR. The biological functions of mtUPR are not confined to mitochondria but are also crucial for the health of the entire cell and even the whole organism. The mtUPR process requires communication between mitochondria and the nucleus, and this phenomenon is highly conserved and has been observed across different species. The abnormal activation or inhibition of mtUPR is closely related to the occurrence and development of a variety of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease and in-depth exploration of the dynamic regulatory role and molecular mechanism of mtUPR is of great significance to the pathogenesis of neurodegenerative diseases. In addition to neuron loss, neurodegenerative diseases are characterized by the accumulation of incorrectly folded proteins forming in the brain such as insoluble fibrils of amyloid beta, phosphorylated tau, or α-synuclein. In different diseases, the molecular pathways of mtUPR are largely conserved, however, the possibility of the existence of differential regulatory factors cannot be excluded. while mtUPR activation is predominantly recognized for its cytoprotective role, it can exert deleterious effects when overstimulated or extended. Chronic mtUPR activity has been linked to mitochondrial dysfunction and increased neuronal vulnerability, thereby contributing to the pathogenesis of diverse neurodegenerative diseases. This review summarizes the fundamental concepts, major inducers, and signaling pathways of the mitochondrial unfolded protein response (mtUPR). We focus on the intrinsic relationship and regulatory patterns between mtUPR and neurodegenerative diseases, providing insights that could aid the development of targeted therapies. Finally, we discuss the challenges and future directions of mtUPR research in this field, aiming to pave the way for new therapeutic breakthroughs for neurodegenerative diseases. The main limitation arises from the experimental models used. Most findings rely on model organisms or cultured cells, which cannot fully reproduce the complexity of human neurons. Future research should therefore focus on three main directions: (i) defining molecular switches that determine whether mtUPR act in protective or detrimental ways, (ii) elucidating the differences in mtUPR molecular pathways across various neurodegenerative diseases models, (iii) establishing robust biomarkers for mtUPR activity.