AbstractSARS‐CoV‐2 may directly and indirectly damage lung tissue and other host organs, but there are few system‐wide, untargeted studies of these effects on the human body. Here, we developed a parallelized mass spectrometry (MS) proteomics workflow enabling the rapid, quantitative analysis of hundreds of virus‐infected FFPE tissues. The first layer of response to SARS‐CoV‐2 in all tissues was dominated by circulating inflammatory molecules. Beyond systemic inflammation, we differentiated between systemic and true tissue‐specific effects to reflect distinct COVID‐19‐associated damage patterns. Proteomic changes in the lungs resembled those of diffuse alveolar damage (DAD) in non‐COVID‐19 patients. Extensive organ‐specific changes were also evident in the kidneys, liver, and lymphatic and vascular systems. Secondary inflammatory effects in the brain were related to rearrangements in neurotransmitter receptors and myelin degradation. These MS‐proteomics‐derived results contribute substantially to our understanding of COVID‐19 pathomechanisms and suggest strategies for organ‐specific therapeutic interventions.