Identification of proteins dysregulated by COVID-19 infection is critically important for better understanding of its pathophysiology, building prognostic models, and identifying new targets. Plasma proteomic profiling of 4,301 proteins was performed in two independent datasets and tested for the association for three COVID-19 outcomes (infection, ventilation, and death). We identified 1,449 proteins consistently associated in both datasets with any of these three outcomes. We subsequently created highly accurate models that distinctively predict infection, ventilation, and death. These proteins were enriched in specific biological processes including cytokine signaling, Alzheimer’s disease, and coronary artery disease. Mendelian randomization and gene network analyses identified eight causal proteins and 141 highly connected hub proteins including 35 with known drug targets. Our findings provide distinctive prognostic biomarkers for two severe COVID-19 outcomes, reveal their relationship to Alzheimer’s disease and coronary artery disease, and identify potential therapeutic targets for COVID-19 outcomes.