SARS-CoV-2 infection causes COVID-19, a severe acute respiratory disease associated with cardiovascular complications including long-term outcomes. The presence of virus in cardiac tissue of patients with COVID-19 suggests this is a direct, rather than secondary, effect of infection. By expressing individual SARS-CoV-2 proteins in the Drosophila heart we demonstrated interaction of virus Nsp6 with host proteins of the MGA/MAX complex (MGA, PCGF6 and TFDP1). Complementing transcriptomic data from the fly heart revealed that this interaction blocks the antagonistic MGA/MAX complex, which shifts the balance towards MYC/MAX and activates glycolysis—with similar findings in mouse cardiomyocytes. Further, the Nsp6-induced glycolysis disrupted cardiac mitochondrial function, known to increase reactive oxygen species (ROS) in heart failure; this could explain COVID-19-associated cardiac pathology. Furthermore, inhibiting the glycolysis pathway by 2-deoxy-D-glucose (2DG) treatment attenuated the Nsp6-induced cardiac phenotype in fly and mice; thus, suggesting glycolysis as a potential pharmacological target for treating COVID-19-associated heart failure.