Current antiviral treatments often target specific viral components, which can lead to the rapid emergence of drug-resistant mutants. Targeting host signaling pathways, including their associated cellular factors, that are important for virus replication is a novel approach toward the development of next-generation antivirals to overcome drug resistance. Various cellular receptor tyrosine kinases (RTKs) have previously been shown to play important roles in mediating viral replication including coronaviruses. In this study, we examined the roles of RTKs in SARS-CoV-2 replication in two cell lines, A549-ACE2 (human lung epithelial cells) and Vero-E6 (African Green Monkey kidney cell), via chemical inhibitors. We showed that the HER2 inhibitor Lapatinib significantly reduced viral replication in both cell lines, the TrkA inhibitor GW441756 was effective only in A549-ACE2 cells, while the EGFR inhibitor Gefitinib had little effect in either cell line. Lapatinib and GW441756 exhibited a high therapeutic index (CC(50)/EC(50) > 10) in A549-ACE2 cells. Time-of-addition experiments indicated that Lapatinib may inhibit the early entry step, whereas GW441756 can affect post-entry steps of the viral life cycle. These findings suggest the important roles of HER2 and TrkA signaling in SARS-CoV-2 infection in human lung epithelial cells and support further investigation of RTK inhibitors as potential COVID-19 treatments.