Perilipins (Plins) are key proteins associated with lipid droplets (LDs) and play a critical role in cellular lipid storage and metabolism. This review explores the interaction between oxidative stress and Plins, highlighting their role in cardiovascular disease. Oxidative stress, caused by an imbalance between reactive oxygen species (ROS) and antioxidants, is a major contributor to cardiac dysfunction, including heart failure, ischemia-reperfusion injury, and diabetic cardiomyopathy. LDs, which store neutral lipids, are coated with Plins, which help regulate lipid availability and protect against lipotoxicity. Recent studies suggest that LD biogenesis helps alleviate oxidative stress by maintaining cellular homeostasis. Plins are involved in various cellular processes, including lipid storage, mitochondrial function, and inflammation. Different Plins (Plin1–5) have distinct roles in oxidative stress and cardiac dysfunction. For example, Plin2 and Plin5 are highly expressed in the heart and are involved in lipid storage and mitochondrial function. Plin5 has been shown to protect the heart from oxidative stress by sequestering fatty acids and reducing ROS production. Plin2 is involved in lipid metabolism and has been linked to metabolic diseases. The regulation of Plins by oxidative stress involves transcriptional and post-translational mechanisms, including the PPAR family of transcription factors. Understanding the role of Plins in oxidative stress and cardiovascular disease could lead to new therapeutic strategies for managing heart failure and other cardiac conditions. The review also discusses the potential of LDs as ROS scavengers and the importance of targeting Plins for antioxidant therapy.Perilipins (Plins) are key proteins associated with lipid droplets (LDs) and play a critical role in cellular lipid storage and metabolism. This review explores the interaction between oxidative stress and Plins, highlighting their role in cardiovascular disease. Oxidative stress, caused by an imbalance between reactive oxygen species (ROS) and antioxidants, is a major contributor to cardiac dysfunction, including heart failure, ischemia-reperfusion injury, and diabetic cardiomyopathy. LDs, which store neutral lipids, are coated with Plins, which help regulate lipid availability and protect against lipotoxicity. Recent studies suggest that LD biogenesis helps alleviate oxidative stress by maintaining cellular homeostasis. Plins are involved in various cellular processes, including lipid storage, mitochondrial function, and inflammation. Different Plins (Plin1–5) have distinct roles in oxidative stress and cardiac dysfunction. For example, Plin2 and Plin5 are highly expressed in the heart and are involved in lipid storage and mitochondrial function. Plin5 has been shown to protect the heart from oxidative stress by sequestering fatty acids and reducing ROS production. Plin2 is involved in lipid metabolism and has been linked to metabolic diseases. The regulation of Plins by oxidative stress involves transcriptional and post-translational mechanisms, including the PPAR family of transcription factors. Understanding the role of Plins in oxidative stress and cardiovascular disease could lead to new therapeutic strategies for managing heart failure and other cardiac conditions. The review also discusses the potential of LDs as ROS scavengers and the importance of targeting Plins for antioxidant therapy.