RATIONALE: Although the global impact of coronavirus disease 2019 (COVID-19) has diminished, cardiovascular complications, such as acute myocardial infarction, remain a critical concern. This case highlights the potential role of COVID-19 in destabilizing preexisting coronary plaques through systemic inflammation and hypercoagulability, offering insights into diagnostic and therapeutic strategies for similar patients. PATIENT CONCERNS: A 41-year-old woman with no prior cardiovascular risk factors presented with sudden-onset chest pain 5 days after a confirmed COVID-19 diagnosis. Initial electrocardiography showed ST-segment changes and troponin I levels were mildly elevated. DIAGNOSIS: Emergency coronary angiography revealed 90% stenosis in the middle segment of left anterior descending artery with thrombus, confirming acute anterior myocardial infarction. Optical coherence tomography identified vulnerable plaque features, including macrophages and cholesterol crystals, without plaque rupture. INTERVENTIONS AND OUTCOMES: Thrombus aspiration and optical coherence tomography-guided drug-eluted balloon angioplasty were performed. Post-procedural multimodal imaging (coronary computed tomography angiogram, cardiac magnetic resonance) demonstrated residual plaque burden and mid-myocardial late gadolinium enhancement, suggesting dual ischemic and inflammatory injuries. Intensive lipid-lowering therapy (alirocumab and rosuvastatin) and dual antiplatelet therapy were also administered. LESSONS: The disease course of the patient suggests that COVID-19 could play a role in the destabilization of atherosclerotic plaques through a high inflammatory status in the blood vessels, leading to a hypercoagulable state and acute myocardial infarction induction. Therefore, monitoring inflammatory markers and administering adequate anti-inflammatory treatments may be necessary for such patients.