Survival after lung transplantation lags that of other solid organ transplants. Long-term survival is hampered primarily due to chronic lung allograft dysfunction (CLAD) development. It remains elusive how (chronic) rejection is organized within the lung graft over time post-transplant. Using a model of orthotopic left lung transplantation in major mismatched mouse strains with daily immunosuppression, we aimed to study the spatiotemporal dynamics of (chronic) rejection, using micro-computed tomography imaging, flow cytometric analyses and spatial proteomics. Endothelial cells demonstrated early activation and destruction (day 7 post-transplant). The accompanying early inflammation at the vascular compartment, progressed towards aberrant tissue repair resulting in irreversible bronchovascular fibrosis and chronic graft dysfunction. We provide new insights in the spatiotemporal dynamics of (chronic) rejection with a vascular-oriented onset that may have future implications for diagnosis and treatment in clinical lung transplantation.