Futile recanalization (FR) after endovascular treatment (EVT) remains a significant challenge for acute ischemic stroke (AIS) with large vessel occlusion (LVO). The pathogenesis of FR has not been well elucidated. We prospectively enrolled anterior circulation LVO-AIS patients who achieved successful recanalization after EVT. The jugular venous blood ipsilateral to stroke was collected before and immediately after recanalization. Plasma proteomic analysis based on liquid chromatography-mass spectrometry was performed using data-independent acquisition method. Differentially expressed proteins (DEPs) among patients with or without FR in the whole or propensity score matching (PSM) cohorts were screened according to the absolute value of fold change ≥1.5 and P value <0.05. We identified 104 and 34 DEPs between patients with or without FR in the whole cohort and PSM cohort, respectively. Bioinformatic analysis indicated that the identified proteins were primarily related to specific biological processes including immune response, complement activation, oxidative stress, lipid metabolism, protein ubiquitylation as well as autophagy, suggesting that these may be mechanisms in FR pathogenesis. Collectively, we discovered proteins that may be potential research targets for FR. The combination of proteomic and bioinformatic analysis could provide a better understanding of the pathogenesis of FR in a comprehensive manner.