Background The mechanisms used by SARS-CoV-2 to induce major adverse cardiac events (MACE) are unknown. Thus, we aimed to determine if SARS-CoV-2 can infect the heart to kill cardiomyocytes and induce MACE in patients with severe COVID-19. Methods This observational prospective cohort study includes experiments with hamsters and human samples from patients with severe COVID-19. Cytokines and serum biomarkers were analyzed in human serum. Cardiac transcriptome analyses were performed in hamsters' hearts. Results From a cohort of 70 patients, MACE was documented in 26% (18/70). Those who developed MACE had higher Log copies/mL of SARS-CoV-2, troponin-I, and pro-BNP in serum. Also, the elevation of IP-10 and a major decrease in levels of IL-17ɑ, IL-6, and IL-1rɑ were observed. No differences were found in the ability of serum antibodies to neutralize viral spike proteins in pseudoviruses from variants of concern. In hamster models, we found a stark increase in viral titers in the hearts 4 days post-infection. The cardiac transcriptome evaluation resulted in the differential expression of ~ 9% of the total transcripts. Analysis of transcriptional changes of the effectors of necroptosis (mixed lineage kinase domain-like, MLKL) and pyroptosis (gasdermin D) showed necroptosis, but not pyroptosis, to be elevated. Active form of MLKL (phosphorylated MLKL, pMLKL) was elevated in hamster hearts and, most importantly, in the serum of MACE patients. Conclusion SARS-CoV-2 can reach the heart during severe COVID-19 and induce necroptosis in the heart of patients with MACE. Thus, pMLKL could be used as a biomarker of cardiac damage and a therapeutic target. Trial registration: Not applicable.