Background and Purpose: Diffusion-weighted imaging-fluid-attenuated inversion recovery (DWI-FLAIR) mismatch is an early sign of acute ischemic stroke. DWI-FLAIR mismatch was reported to be valuable to select patients with unknown onset stroke who are eligible to receive intravenous thrombolysis (IVT), but its utility is less studied in patients undergoing mechanical thrombectomy (MT) for acute large vessel occlusion (LVO). We thus investigated the functional outcomes at 90 days between patients with DWI-FLAIR mismatch and those with match who underwent MT for LVO. Methods: We conducted a historical cohort study in consecutive patients who were evaluated by magnetic resonance imaging for suspected stroke at a single center. We enrolled patients with occlusion of internal carotid artery or horizontal or vertical segment of middle cerebral artery who underwent MT within 24 h after they were last known to be well. DWI-FLAIR mismatch was defined when a visible acute ischemic lesion was present on DWI without traceable parenchymal hyperintensity on FLAIR. Image analysis was done by 2 stroke neurologists independently. We estimated the adjusted odds ratio (OR) of DWI-FLAIR mismatch relative to DWI-FLAIR match for moderate outcome defined as modified Rankin Scale (mRS) 0–3, favorable outcome defined as mRS 0–2 and mortality at 90 days after the onset, and symptomatic intracranial hemorrhage (sICH) within 72 h after the onset. Results: Of the 380 patients who received MT, 202 were included. Patients with DWI-FLAIR mismatch (146 [72%]) had significantly higher baseline National Institutes of Health Stroke Scale (median 16 vs. 13, p = 0.01), more transferred-in (78 vs. 63%, p = 0.02), more IVT (45 vs. 18%, p = 0.0003), more cardioembolism (69 vs. 54%, p = 0.03), and shorter onset-to-hospital door times (median 175 vs. 371 min, p < 0.0001) than patients with DWI-FLAIR match. Patients with DWI-FLAIR mismatch had more moderate outcome than those with DWI-FLAIR match (61 vs. 52%, p = 0.24), and the adjusted OR was 3.12 (95% confidence interval [CI]: 1.35–7.19, p = 0.008). sICH within 72 h was less frequent in the DWI-FLAIR mismatch group (10 vs. 20%, p = 0.06), with an adjusted OR of 0.36 (95% CI: 0.13–0.97, p = 0.044). The adjusted ORs for favorable outcome and mortality were 0.87 (95% CI: 0.39–1.94, p = 0.73) and 0.63 (95% CI: 0.20–2.05, p = 0.44), respectively. Conclusions: DWI-FLAIR mismatch was associated with more moderate outcome and less sICH in the adjusted analysis in patients receiving MT for acute LVO. DWI-FLAIR mismatch could be useful to select patients with unknown onset stroke who are eligible to receive MT for acute LVO.