In this study, we aimed to explore methylcobalamin (MeCbl), a common treatment for peripheral nerve injuries, and its impact on macrophage phenotypes (inflammatory or anti-inflammatory) at nerve injury sites and the underlying mechanism. Using a sciatic nerve crush injury model in 6-week-old Wistar rats, we administered either saline (control group) or MeCbl (MeCbl group) via osmotic pumps for sustained systemic delivery. We assessed macrophage phenotypes in transverse sections of the sciatic nerve up to 14 days post-surgery using fluorescence immunostaining. In vitro, we induced inflammatory or anti-inflammatory phenotypes in mouse macrophage cell lines with LPS or IL-4, respectively. Then, we co-administered MeCbl (1 nM-1 mM) and assessed macrophage phenotype protein expression using Western blotting. Additionally, we investigated MeCbl's effects on intracellular signaling molecules and its involvement in Ras activation through the methylation pathway primarily using Western blotting. The MeCbl group exhibited a significant decrease in total macrophage count and inflammatory macrophage count, coupled with a notable increase in anti-inflammatory macrophage count at the nerve injury site compared to the control group in vivo. In vitro, MeCbl administration at approximately 100 nM significantly decreased inflammatory marker protein expression while increasing anti-inflammatory marker protein expression. MeCbl (100 nM) administration induced Ras activation and facilitated Akt phosphorylation in signaling molecules, with these effects being nullified by methylation pathway inhibition. Our findings suggest that during peripheral nerve injury regeneration, MeCbl promotes Akt phosphorylation via Ras activation through the methylation pathway, consequently shifting macrophage phenotype toward an anti-inflammatory state.