<p>Radiotherapy and chemotherapy are primary cancer treatments, yet hematopoietic damage induced by these therapies is increasingly prevalent. Under physiological conditions, macrophages serve as key regulators of hematopoietic stem cells (HSCs) and the hematopoietic microenvironment. Through bidirectional regulatory mechanisms driven by functional heterogeneity among macrophage subtypes, they dynamically modulate hematopoiesis. This includes maintaining HSCs quiescence and mobilization, ensuring HSCs quality control, regulating HSCs localization, and balancing inflammatory responses with microenvironmental remodeling within the hematopoietic niche. Following chemoradiation therapy, macrophages exert bidirectional effects on hematopoietic damage. On one hand, they exacerbate injury by intensifying HSCs damage, disrupting hematopoietic microenvironment homeostasis, and inducing myeloid bias. On the other hand, they support hematopoietic recovery through mechanisms such as maintaining HSCs function and promoting hematopoietic niche reconstruction. Furthermore, we summarize the application potential of natural products and small molecules based on macrophage regulation in improving hematopoietic damage after chemoradiotherapy, aiming to provide new insights for developing clinical treatment strategies. Future research should further elucidate the molecular mechanisms of macrophage regulation of hematopoiesis after chemoradiotherapy and explore precision therapeutic strategies targeting macrophages to optimize prevention and treatment protocols for bone marrow hematopoietic damage following chemoradiotherapy.</p> Graphical abstract <p></p>