The intervertebral disc is the largest avascular structure in the body, and cells within the disc rely on diffusive transport via vasculature located within the vertebral endplate to receive nutrients, eliminate waste products, and maintain disc health. However, the mechanisms by which small molecule transport into the disc occurs in vivo and how these parameters change with disc degeneration remain understudied. Here, we utilize an in vivo rabbit puncture disc degeneration model to study these interactions and provide evidence that remodeling of the endplate adjacent to the disc occurs concomitant with degeneration. Our results identify significant increases in endplate bone volume fraction, increases in microscale stiffness of the soft tissue interfaces between the disc and vertebral bone, and reductions in endplate vascularity and small molecule transport into the disc as a function of degenerative state. A neural network model identified changes in diffusion into the disc as the most significant predictor of disc degeneration. These findings support the critical role of trans‐endplate transport in disease progression and will improve patient selection to direct appropriate surgical intervention and inform new therapeutic approaches to improve disc health.