Endothelial cells (ECs) are crucial for vascular health, regulating blood flow, nutrient exchange, and modulating immune responses and inflammation. The impairment of these processes causes the endothelial dysfunction (ED) characterized by oxidative stress, inflammation, vascular permeability, and extracellular matrix remodeling. While primary ECs have been widely used to study ED in vitro, their limitations—such as short lifespan and donor variability—pose challenges. In this context, induced iECs derived from induced pluripotent stem cells offer an innovative solution, providing an unlimited source of ECs to explore disease-specific features of ED. Recent advancements in 3D models and microfluidic systems have enhanced the physiological relevance of iEC-based models by better mimicking the vascular microenvironment. These innovations bridge the gap between understanding ED mechanisms and drug developing and screening to prevent or treat ED. This review highlights the current state of iEC technology as a model to study ED in vascular and non-vascular disorders, including diabetes, cardiovascular, and neurodegenerative diseases.