Abstract Thrombosis, the obstruction of blood flow due to the formation of clot in blood vessels, accounts for 1 in 4 deaths worldwide. In particular, venous thrombi occur in deep veins most often in the legs or arms and is commonly known as deep vein thrombosis (DVT). DVT and pulmonary embolism are collectively referred to as venous thromboembolism (VTE) in which a part of the venous thrombus breaks off, travel to the lungs, and lodge in pulmonary arteries. VTE is the 3rd leading cause of cardiovascular-related deaths globally with estimates of >500,000 deaths in the United States every year. VTE is reported to be the leading cause of disability-adjusted life years lost in hospitalized patients. Despite the large amount of capital invested in drug development, very few drugs are ultimately proven useful in humans. Such a low yield occurs largely because planar cell culture and animal models for testing the drugs oftentimes fail to reflect human physiology/pathology. In contrast, three-dimensional (3D) human cell-based in vitro models have been increasingly adopted to improve drug testing by recapitulating physiological and pathological parameters of their human counterparts. In addition to the development of engineered human- based microtissues, real-time, in situ, non-invasive volumetric monitoring of the behaviors of the engineered vascular models and their responses towards viral infection/drug treatment is a key capacity to achieve high(er)-throughput and accurate in vitro screening of promising drug candidates. Here we propose to harness our unique expertise in engineered in vitro human vascular tissue models and high-speed label-free imaging of thrombosis with further aid by strong experiences in clinical hematology and anticoagulation management in patients. Together, we will create an enabling and first-of-its-kind high(er)- throughput real-time imaging-integrated thrombosis-on-chip model to study thrombosis and potential therapeutic agents, taking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as a timely example to instruct future preparedness for pandemics and other vascular disorders.