Cardiovascular/heart tissue and cells are subjected to dynamic forces from very early development, without pause, for the entire life of the animal or person and are characterized by being very sensitive to the mechanical properties of the surrounding tissue. Most cardiovascular diseases are characterized by important modifications that occur at the level of extracellular matrix (ECM) components that correlate with an increase in tissue stiffness and contribute to impaired heart function. Additionally, several studies show that cardiovascular/heart cells themselves can undergo modifications in their morphology and mechanical properties in various biological processes as well as in different pathologies. This mini review illustrates how atomic force microscopy (AFM) indentation can be used in combination with different experimental strategies to access the mechanical properties of cardiovascular/heart tissue and cells, which can help in understanding the different biological and pathological processes in these types of tissues and cells in depth.