BACKGROUND: Carotid arteriosclerosis is common, with interventional therapy being the primary treatment. However, postoperative restenosis and poor stent patency, related to vascular inflammation involving MAPK and PP2A, limit success. Formononetin (FOR) may offer a novel approach by activating PP2A and inhibiting MAPK, reducing inflammation and improving outcomes. METHODS: Rats were divided into sham and carotid artery balloon injury (CABI) groups, with the latter receiving various concentrations of FOR. Vascular damage and inflammation were assessed using HE staining, ELISA, Western blot, and immunohistochemistry. HUVECs were treated with Ox-LDL to induce injury, followed by FOR (10-40 μM) and the MAPK inhibitor U0126. PP2A and MAPK expression were analyzed via Western blot and immunofluorescence. . RESULTS: HE staining showed carotid lumen narrowing and tissue damage in the model group, which improved with FOR treatment. ELISA revealed reduced IL-6 and TNF-α levels post-CABI with FOR. FOR also reversed the decrease of PP2A and increased MAPK expression, along with reduced ERK1/2 phosphorylation. Conclusion FOR reduces vascular damage and inflammation after CABI via the PP2A/MAPK axis, enhancing vascular remodeling and restoring protein expression. FOR shows promise as a therapeutic agent for vascular injuries. CONCLUSION: FOR can effectively reduce vascular damage and inflammation after coronary artery bypass grafting through the PP2A/MAPK axis, enhance vascular remodeling, and restore protein expression profiles. These findings suggest FOR as a promising therapeutic agent for vascular injuries.