Obesity and its related comorbidities, collectively defined as metabolic syndrome (MetS), represent a major health concern due to their strong association with increased cardiometabolic risk. A defining feature of obesity and MetS is the excessive production of reactive oxygen species and reactive nitrogen species, resulting in systemic oxidative stress (OS) and nitrosative stress (NS). In the heart, OS and NS induce structural and conformational alterations in proteins, referred to as oxidative post-translational modifications (oxPTMs). These modifications disrupt protein function, thereby impairing essential cellular processes and ultimately contributing to diastolic and systolic dysfunction. Several proteins critical for cardiac function have been identified as targets of oxPTMs in the context of obesity and MetS. Among the most studied are mitochondrial proteins such as dynamin-related protein 1 (Drp1), respiratory chain complexes I, II, and IV, and creatine kinase, as well as Ca2+-handling proteins including sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and ryanodine receptors (RyR2). This chapter summarizes current knowledge on the mechanisms underlying cardiac dysfunction in obesity and MetS, with a particular emphasis on OS and its damaging effects on mitochondrial metabolism and Ca2+ handling. Finally, we provide an update on recent findings regarding natural antioxidants and mitochondria-targeted antioxidant therapies, highlighting their potential as treatment strategies for cardiovascular diseases associated with obesity and MetS.