Heart failure (HF) represents the terminal stage of various cardiovascular diseases, and one of its core characteristics is the structural and functional disorders of cardiomyocytes. In recent years, with the advancement of molecular biology and genetic technologies, the research focus has shifted from the macroscopic organ failure to the microscopic molecular networks, including gene expression regulation, metabolic remodeling, immune-inflammatory responses, and dynamic changes in the extracellular matrix and cytoskeletal proteins. As the "internal scaffold" of cardiomyocytes, cytoskeletal proteins have increasingly demonstrated their critical role in the occurrence and progression of HF. This review aims to systematically summarize the current research status of pathological remodeling, molecular mechanisms, and potential therapeutic targets of the cardiomyocyte cytoskeleton (including microfilaments, microtubules, and intermediate filaments) as well as the extracellular matrix in HF. It also outlooks future research directions, providing references for the basic research and clinical treatment of HF, with the expectation of offering new theoretical foundations and directions for the precise prevention and treatment of HF.