Skeletal muscle regeneration is a complex interplay between various cell types including invading macrophages. Their recruitment to damaged tissues upon acute sterile injuries is necessary for necrotic debris clearance and for coordination of tissue regeneration. This highly dynamic process is characterized by an in‐situ transition of infiltrating monocytes from an inflammatory (Ly6Chigh) to a repair (Ly6Clow) macrophage phenotype. The importance of the macrophage phenotypic shift and the cross‐talk of the local muscle tissue with the infiltrating macrophages during tissue regeneration upon injury are not fully understood and their study lacks adequate methodology. Here, using an acute sterile skeletal muscle injury model combined with irradiation, bone marrow transplantation and in vivo imaging we show that preserved muscle integrity and cell composition prior to the injury is necessary for repair macrophage phenotypic transition and subsequently for proper and complete tissue regeneration. Importantly, by using a model of in vivo ablation of PAX7 positive cells, we show that this radiosensitive skeletal muscle progenitor pool contributes to macrophage phenotypic transition following acute sterile muscle injury. In addition, local muscle tissue radioprotection by lead shielding during irradiation preserves normal macrophage transition dynamics and subsequently muscle tissue regeneration. Taken together, our data suggest the existence of a more extensive and reciprocal cross‐talk between muscle tissue compartments, including satellite cells, and infiltrating myeloid cells upon tissue damage. These interactions are shaping the macrophages in‐situ phenotypic shift, which is indispensable for normal muscle tissue repair dynamics. This article is protected by copyright. All rights reserved