A coronary artery calcium (CAC) score of 0 is generally indicative of a low risk for both all-cause mortality and cardiovascular events, often serving as a basis for excluding obstructive coronary artery disease (CAD). Although isolated cases of coronary involvement have been reported in patients with a CAC score of 0, the incidence of extensive multivessel disease under these circumstances is exceedingly rare. A 48-year-old man with diabetes and hypercholesterolemia presented with atypical non-exertional left-sided chest pain. Despite a nonspecific ECG, a HEART score of 3, and a zero CAC score on echocardiography, coronary computed tomography angiography (CCTA) revealed multiple non-calcified plaques in the right coronary artery (RCA), right posterior descending coronary artery (RPDA), and left circumflex artery (LCX). The patient underwent staged percutaneous coronary intervention with drug-eluting stents, resulting in complete resolution of the stenosis. At the one-month follow-up, he remained symptom-free and tolerated the medication regimen well. This case report demonstrates that a zero CAC score should not preclude further evaluation in high-risk symptomatic patients. Extensive non-calcified plaques causing significant luminal obstruction underscore the limitations of CAC scoring, highlighting the need for additional imaging modalities, such as CCTA, to achieve timely and accurate diagnoses and appropriate therapeutic interventions.