Radiation-induced lymphopenia (RIL) is a common side effect after radiotherapy in cancer patients and is associated with inferior outcome. However, the mechanism causing RIL is insufficiently understood, but many groups turn to murine studies to study this phenomenon in more detail. Yet, findings are scattered and difficult to interpret in absence of a systematic framework into which these findings can be integrated. Therefore, I set out to develop a whole-body compartmental model of lymphocyte migration in murine animals, combining a rapidly exchanging blood circulation model with a slowly exchanging lymph flow model. Each compartment was associated to its corresponding 3D organ structure using detailed murine phantom meshes including secondary lymphoid organs (SLOs) such as lymph nodes and Peyer’s patches. Using a stochastic representation of the lymphocyte migration model, the trajectories of lymphocytes migrating through the murine phantom were simulated. In parallel, an irradiation module was developed to computationally reproduce small animal irradiation plans using either photon or proton beams. Combining these computational tools allowed for the dynamical accumulation of lymphocyte dose in hypothetical treatment scenarios. Lymphocytes survive radiation as dose-dependent probabilistic events and viable ones redistribute across compartments. Contrary to common belief, the model indicates that RIL is caused by irradiation of SLOs which, through lymphocyte recirculation, is eventually reflected in the blood counts.