Background Cardiac dysfunction is a prominent feature of multisystem inflammatory syndrome in children (MIS‐C), yet the etiology is poorly understood. We determined whether dysfunction is global or regional, and whether it is associated with the cytokine milieu, microangiopathy, or severity of shock. Methods and Results We analyzed echocardiographic parameters of myocardial deformation and compared global and segmental left ventricular strain between 43 cases with MIS‐C ≤18 years old and 40 controls. Primary outcomes included left ventricular global longitudinal strain, right ventricular free wall strain), and left atrial strain. We evaluated relationships between strain and profiles of 10 proinflammatory cytokines, microangiopathic features (soluble C5b9), and vasoactive‐inotropic requirements. Compared with controls, cases with MIS‐C had significant impairments in all parameters of systolic and diastolic function. 65% of cases with MIS‐C had abnormal left ventricular function ( | global longitudinal strain | <17%), although elevations of cytokines were modest. All left ventricular segments were involved, without apical or basal dominance to suggest acute stress cardiomyopathy. Worse global longitudinal strain correlated with higher ratios of interleukin‐6 (ρ −0.43) and interleukin‐8 (ρ −0.43) to total hypercytokinemia, but not absolute levels of interleukin‐6 or interleukin‐8, or total hypercytokinemia. Similarly, worse right ventricular free wall strain correlated with higher relative interleukin‐8 expression (ρ −0.59). There were no significant associations between function and microangiopathy or vasoactive‐inotropic requirements. Conclusions Myocardial function is globally decreased in MIS‐C and not explained by acute stress cardiomyopathy. Cardiac dysfunction may be driven by the relative skew of the immune response toward interleukin‐6 and interleukin‐8 pathways, more so than degree of hyperinflammation, refining the current paradigm of myocardial involvement in MIS‐C.