Background: Endothelial dysfunction, characterized by impaired flow-mediated vasodilation (FMD), is associated with atherosclerosis. However, the relationship between FMD, plaque morphology, and clinical outcomes in patients with acute coronary syndrome (ACS) remains underexplored. This study aims to investigate the influence of FMD on the morphology of culprit plaques and subsequent clinical outcomes in patients with ACS. Methods: This study enrolled 426 of 2482 patients who presented with ACS and subsequently underwent both preintervention FMD and optical coherence tomography (OCT) between May 2020 and July 2022. Impaired FMD was defined as an FMD% less than 7.0%. Major adverse cardiac events (MACEs) included cardiac death, nonfatal myocardial infarction, revascularization, or rehospitalization for angina. Results: Within a one-year follow-up, 34 (8.0%) patients experienced MACEs. The median FMD% was 4.0 (interquartile range 2.6–7.0). Among the patients, 225 (52.8%) were diagnosed with plaque rupture (PR), 161 (37.8%) with plaque erosion (PE), and 25 (5.9%) with calcified nodules (CN). Impaired FMD was found to be associated with plaque rupture (odds ratio [OR] = 4.22, 95% confidence interval [CI]: 2.07–6.72, p = 0.012) after adjusting for potential confounding factors. Furthermore, impaired FMD was linked to an increased incidence of MACEs (hazard ratio [HR] = 3.12, 95% CI: 1.27–6.58, p = 0.039). Conclusions: Impaired FMD was observed in three quarters of ACS patients and can serve as a noninvasive predictor of plaque rupture and risk for future adverse cardiac outcomes.