The pursuit of exploring cardiac morphogenesis and remodeling in its entirety and in real time has posed a persistent optical challenge in cardiac development and regeneration research. The emergence of light-sheet microscopy (LSM) has provided unparalleled advantages in spatial resolution, imaging speed, field of view, and depth of field. The representative design of decoupled illumination and detection further allows for minimal photobleaching and phototoxicity, in contrast to conventional optical imaging approaches. This strategy enhances in vivo visualization from the developing circulation system in live zebrafish embryos to ex vivo investigation of the micro-structure of optically cleared rodent cardiovascular anatomy. We hereby introduce basic concepts of LSM and its numerous applications, showcasing representative studies that have advanced the understanding of developmental and pathological processes in hearts, as well as vascular networks across various levels. Through these investigations, we discuss the potential and limitations of multi-scale LSM in unveiling cardiovascular structure and function. Overall, the versatile framework of LSM holds promise for elucidating intricate cardiovascular systems, providing insights into cardiac morphogenesis and disease pathogenesis.