An increased risk of atherosclerotic and thrombotic complications characterizes connective tissue diseases. Endothelial dysfunction is the basis for the initiation and progression of atherosclerosis and thrombosis. We present systemic lupus erythematosus (SLE) as a model rheumatic disease with endothelial dysfunction and discuss its mechanisms, factors that influence the early onset and rapid progression of atherosclerosis, and the increased risk of thromboembolic events. We focus on established methods to improve endothelium function, including statins, antiplatelet, and antithrombotic therapy. Hypercoagulable and hypofibrinolitic states and a hyperinflammatory response characterize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Several pathogenic mechanisms are typical for an acute phase of Covid-19 post-Covid syndrome and connective tissue diseases: endothelial dysfunction, elevated antiphospholipid antibody titer, activation of the complement system, and formation of extracellular neutrophil traps (NET). The current review discusses the mechanisms underlying SLE and the COVID-19 in the context of endothelial function, atherosclerosis, and thrombosis (Graphical abstract).