The measurement of fractional flow reserve (FFR) and superficial wall stress (SWS) identifies inducible myocardial ischemia and plaque vulnerability, respectively. A simultaneous evaluation of both FFR and SWS is still lacking, while it may have a major impact on therapy. A new computational model of one-way fluid–structure interaction (FSI) was implemented and used to perform a total of 54 analyses in virtual coronary lesion models, based on plaque compositions, arterial remodeling patterns, and stenosis morphologies under physiological conditions. Due to a greater lumen dilation and more induced strain, FFR in the lipid-rich lesions (0.81 ± 0.15) was higher than that in fibrous lesions (0.79 ± 0.16, P = 0.001) and calcified lesions (0.79 ± 0.16, P = 0.001). Four types of lesions were further defined, based on the combination of cutoff values for FFR (0.80) and maximum relative SWS (30 kPa): The level of risk increased from (1) plaques with mild-to-moderate stenosis but negative remodeling for lipid-rich (Type A: non-ischemic, stable) to (2) lipid-rich plaques with mild-to-moderate stenosis and without-to-positive remodeling (Type B: non-ischemic, unstable) or plaques with severe stenosis but negative remodeling for lipid-rich (Type C: ischemic, stable) to (3) lipid-rich plaques with severe stenosis and without-to-positive remodeling (Type D: ischemic, unstable). The analysis of FSI to simultaneously evaluate inducible myocardial ischemia and plaque stability may be useful to identify coronary lesions at a high risk and to ultimately optimize treatment. Further research is warranted to assess whether a more aggressive treatment may improve the prognosis of patients with non-ischemic, intermediate, and unstable lesions.