Skin, the largest organ in a human body, exhibits high structural complexity for its unique functions. Hair follicles, one of the skin appendages, are a miniorgan with distinct lifelong cyclic growth that are fueled by their resident stem cells. The activity of hair follicle stem cells are tightly regulated by their niche microenvironment for physiological growth as well as regeneration after injuries. Therefore, hair follicles provide an excellent model for the research of stem cell biology. The telogen hair follicles, activated by many initiators, undergo cell proliferation and become anagen hair follicles, and the researches of these initiators have become popular and well development recently. This study is aimed at exploring how hair follicles react to irritation to interfollicular epidermis to regenerate from telogen to anagen. We employed the irritant sodium dodecyl sulfate (SDS) to induce irritant contact dermatitis during telogen phase. We found that, after SDS treatment, hair follicle stem cells were activated and hair follicles entered anagen prematurely. This was associated with infiltration of immune cells, including neutrophils and macrophages, in the perifollicular environment. Depletion of macrophages, but not neutrophils, prohibited SDS-induced anagen entry, indicating that activated macrophages are essential for hair follicle stem cell activation by SDS treatment. Molecularly, increased expression of vascular endothelial growth factor (VEGF) was associated with macrophage infiltration. Inhibition of VEGF signaling delayed SDS-induced anagen entry. In summary, this study shows that hair follicles are able to initiate a protective regenerative reaction in the presence of irritation to interfollicular epidermis. Activation of macrophages and VEGF signaling are involved in activating hair follicle stem cells.