AbstractDespite the increasing incidence of heart failure, advancements in mechanical circulatory support have become minimal. A new type of mechanical circulatory support, direct cardiac compression, is a novel support paradigm that involves a soft deformable cup around the ventricles, compressing it during systole. No group has yet investigated the biomechanical consequences of such an approach. This article uses a multiscale cardiac simulation software to create a patient‐specific beating heart dilated cardiomyopathy model. Left and right ventricle (LV and RV) forces are applied parametrically, to a maximum of 2.9 and 0.46 kPa on each ventricle, respectively. Compression increased the ejection fraction in the left and right ventricles from 15.3% and 27.4% to 24.8% and 38.7%, respectively. During applied compression, the LV freewall thickening increased while the RV decreased; this was found to be due to a change in the balance of the preload and afterload in the freewalls. Principal strain renderings demonstrated strain concentrations on the anterior and posterior LV freewall. Strains in these regions were found to exponentially increase after 0.75 normalized LV force was applied. Component analysis of these strains illuminated a shift in the dominating strain from transmural to cross fiber once 0.75 normalized LV force is exceeded. An optimization plot was created by nondimensionalizing the stroke volume and maximum principal strain for each compression profile, selecting five potential compression schemes. This work demonstrates not only the importance of a computational approach to direct cardiac compression but a framework for tailoring compression profiles to patients.