SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions. Display omitted •Kinase inhibitor screen identified 34 compounds with anti-SARS-CoV-2 activity•Inhibitors targeted mTOR-PI3K-AKT and DNA-damage response (DDR) signaling pathways•ATR kinase inhibitor berzosertib blocked SARS-CoV-1, SARS-CoV-2, and MERS-CoV infection•Treatment with berzosertib blocks SARS-CoV-2 at post-entry level in epithelial cells Garcia et al. screen a library of drug compounds and identify SARS-CoV-2-specific antiviral agents. These drugs have been shown to modulate cellular signaling cascades, including mTOR-PI3K-AKT and DNA-damage response (DDR) pathways. A highly effective drug candidate, berzosertib, blocked multiple coronaviruses, such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV, thus providing a potential therapeutic against COVID-19.