Recent studies indicate the importance of the signal relay from macrophages towards Schwann cells in axon regeneration after peripheral nerve injury. However, the molecular mechanisms underlying axon regeneration via macrophage-Schwann cell communication remain largely unclear. Here, we explored macrophage-derived molecules relevant to axon regeneration. After inferior alveolar nerve transection (IANX), the rats showed hypoesthesia in the lower lip, which was recovered from 10 days after IANX by an intrinsic regeneration capacity. In contrast, macrophage ablation caused delayed nerve regrowth. Furthermore, c-Jun-positive Schwann cells, a repair phenotype, disappeared after the removal of macrophages. Cathepsin S (CTSS) from macrophages promoted recovery from hypoesthesia and cleaved ephrin B2 on fibroblasts. EphB2, a receptor of ephrin B2, was expressed in Schwann cells. Accelerated recovery from hypoesthesia after IANX following CTSS treatment was prevented by neutralization of ephrin B2. These results suggest that CTSS from macrophages liberates ephrin B2 which in turn facilitates axon regeneration in the orofacial regions. Our results lead to the development of novel therapeutics for hypoesthesia caused by nerve injury targeting CTSS.