Human red blood cells (RBCs) are endowed with extreme deformability, enabling them to safely negotiate the narrowest capillaries without sustaining damage. However, in the contexts of cellular aging and various blood disorders, defects in the RBC membrane impair microcirculatory flow and contribute to vascular complications. Employing an integrated methodology of dynamic microfluidics and multiscale simulations, we investigated the biomechanics and flow dynamics of RBCs under physiological and pathological conditions. Our results demonstrate that RBCs undergo extreme deformation within the microvasculature and establish membrane integrity as a critical determinant of blood flow regulation.