Coronavirus spike protein is a very important surface protein of coronavirus, which includes two subunits, S1 and S2. The S1 contains the receptor binding domain (RBD) which can bind to the human angiotensin-converting enzyme 2 (ACE2) protein on the surface of human cells and then infect cells. Spike protein has many different conformational states, constantly changing between the inactive conformation of a glycan-shielded “down” and the activated conformation of an exposed “up”. The RBDs must transition from a “down” to an “up” state for the receptor binding motif (RBM) to be accessible for ACE2 binding. Traditional Chinese Medicine (TCM) plays an important role in the prevention and treatment of COVID-19, and has the advantage of obtaining targeted natural active compounds from it. Qihuang Biwen Prescription (QHBWP) has the effects of invigorating qi, consolidating exterior, moistening dryness and detoxifying, which is widely admitted and used in the prevention of COVID-19, with significant effect. Therefore, we hypothesized that the spike protein is a key target for QHWDP to exert preventive effects, and further research was conducted using pseudovirus experiments combined with computer-aided drug design.