Global health security has been challenged by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. Due to the lengthy process of generating vaccinations, it is vital to reposition currently available drugs in order to relieve anti-epidemic tensions and accelerate the development of therapies for Coronavirus Disease 2019 (COVID-19), the public threat caused by SARS-CoV-2. High throughput screening techniques have established their roles in the evaluation of already available medications and the search for novel potential agents with desirable chemical space and more cost-effectiveness. Here, we present the architectural aspects of high-throughput screening for SARS-CoV-2 inhibitors, especially three generations of virtual screening methodologies with structural dynamics: ligand-based screening, receptor-based screening, and machine learning (ML)-based scoring functions (SFs). By outlining the benefits and drawbacks, we hope that researchers will be motivated to adopt these methods in the development of novel anti-SARS-CoV-2 agents.