Near-infrared optical imaging methods have shown promise for monitoring response to neoadjuvant chemotherapy (NAC) for breast cancer, with endogenous contrast coming from oxy- and deoxyhemoglobin. Spatial frequency domain imaging (SFDI) could be used to detect this contrast in a low-cost and portable format, but it has limited imaging depth. It is possible that local tissue compression could be used to reduce the effective tumor depth. To evaluate the potential of SFDI for therapy response prediction, we aim to predict how changes to tumor size, stiffness, and hemoglobin concentration would be reflected in contrast measured by SFDI under tissue compression. Finite element analysis of compression on an inclusion-containing soft material is combined with Monte Carlo simulation to predict the measured optical contrast. When the effect of compression on blood volume is not considered, contrast gain from compression increases with the size and stiffness of the inclusion and decreases with the inclusion depth. With a model of reduction of blood volume from compression, compression reduces imaging contrast, an effect that is greater for larger inclusions and stiffer inclusions at shallower depths. This computational modeling study represents a first step toward tracking tumor changes induced by NAC using SFDI and local compression.