Direct myocardial and vascular injuries due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-driven inflammation is the leading cause of acute cardiac injury associated with coronavirus disease 2019 (COVID-19). However, in-depth knowledge of the injury characteristics of the heart affected by inflammation is lacking. In this study, using a quantitative spatial proteomics strategy that combines comparative anatomy, laser-capture microdissection, and histological examination, we establish a region-resolved proteome map of the myocardia and microvessels with obvious inflammatory cells from hearts of patients with COVID-19. A series of molecular dysfunctions of myocardia and microvessels is observed in different cardiac regions. The myocardia and microvessels of the left atrial are the most susceptible to virus infection and inflammatory storm, suggesting more attention should be paid to the lesion and treatment of these two parts. These results can guide in improving clinical treatments for cardiovascular diseases associated with COVID-19. Display omitted •Spatial proteome maps of COVID-19 myocardia and microvessels are established•SARS-CoV-2-driven inflammation leads to region-resolved dysfunction of the heart•Mechanisms of dysregulated contraction, conduction, and circulation are elaborated•Myocardia and microvessels of the left atrium are affected by inflammation the most Leng et al. establish a region-resolved proteome map of the inflammatory myocardia and microvessels of COVID-19 hearts. The myocardia and microvessels of the left atrium are the most affected by inflammation storm. These results could provide guidance in improvement of clinical treatments for cardiovascular diseases associated with COVID-19.