Mitochondrial dysfunction is a key feature of heart failure (HF), contributing to a progressive decline in bioenergetic reserve capacity and disease progression. This dysfunction leads to increased oxidative stress, which causes cardiomyocyte apoptosis, calcium homeostasis dysregulation, protein and lipid damage, mitochondrial DNA leakage, and inflammatory responses. These processes contribute to cardiac remodeling and failure. Neurohormonal dysregulation, including angiotensin II, endothelin-1, and sympatho-adrenergic overactivation, exacerbates the condition by promoting ventricular cardiomyocyte hypertrophy and cellular damage. The review discusses the pathophysiological mechanisms of mitochondrial dysfunction in HF, focusing on oxidative stress, membrane potential dynamics, and their association with HF development. It also explores the potential of mitochondria as therapeutic targets, highlighting the role of fatty acid oxidation, mitochondrial quality control, and antioxidant strategies. Dysregulation of fatty acid oxidation in HF leads to energy inefficiency and increased ROS production, contributing to mitochondrial dysfunction. Hyperglycemia in diabetes further exacerbates mitochondrial dysfunction by increasing ROS production and impairing oxidative phosphorylation. Mitochondrial dysfunction also affects ion dynamics, such as calcium homeostasis, leading to mitochondrial damage and arrhythmias. ROS-induced mitochondrial damage contributes to inflammation, fibrosis, and cellular apoptosis, which worsen HF. Therapeutic approaches targeting mitochondria include fatty acid metabolic regulators, antioxidants, and mitochondrial quality control agents. These strategies aim to improve mitochondrial function, reduce ROS production, and restore energy homeostasis in HF. The review emphasizes the importance of mitochondrial dysfunction in HF and highlights potential therapeutic interventions targeting mitochondrial pathways.Mitochondrial dysfunction is a key feature of heart failure (HF), contributing to a progressive decline in bioenergetic reserve capacity and disease progression. This dysfunction leads to increased oxidative stress, which causes cardiomyocyte apoptosis, calcium homeostasis dysregulation, protein and lipid damage, mitochondrial DNA leakage, and inflammatory responses. These processes contribute to cardiac remodeling and failure. Neurohormonal dysregulation, including angiotensin II, endothelin-1, and sympatho-adrenergic overactivation, exacerbates the condition by promoting ventricular cardiomyocyte hypertrophy and cellular damage. The review discusses the pathophysiological mechanisms of mitochondrial dysfunction in HF, focusing on oxidative stress, membrane potential dynamics, and their association with HF development. It also explores the potential of mitochondria as therapeutic targets, highlighting the role of fatty acid oxidation, mitochondrial quality control, and antioxidant strategies. Dysregulation of fatty acid oxidation in HF leads to energy inefficiency and increased ROS production, contributing to mitochondrial dysfunction. Hyperglycemia in diabetes further exacerbates mitochondrial dysfunction by increasing ROS production and impairing oxidative phosphorylation. Mitochondrial dysfunction also affects ion dynamics, such as calcium homeostasis, leading to mitochondrial damage and arrhythmias. ROS-induced mitochondrial damage contributes to inflammation, fibrosis, and cellular apoptosis, which worsen HF. Therapeutic approaches targeting mitochondria include fatty acid metabolic regulators, antioxidants, and mitochondrial quality control agents. These strategies aim to improve mitochondrial function, reduce ROS production, and restore energy homeostasis in HF. The review emphasizes the importance of mitochondrial dysfunction in HF and highlights potential therapeutic interventions targeting mitochondrial pathways.