The pandemic of coronavirus disease 2019 (COVID-19) is no longer a global health emergency, but variants of the causative agent (severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2) are still circulating today. However, only three partially effective antiviral drugs have been approved or authorized by the United States Food and Drug Administration (FDA) to treat COVID-19 (i.e., remdesivir, Paxlovid and molnupiravir). This study focuses on the discovery of small molecular inhibitors targeting Nsp13, which is an RNA helicase essential to SARS-CoV-2 replication and transcription. A cost-effective thermal shift assay (TSA) was employed in primary high-throughput screening (HTS) of 1970 compounds (10 μM), by which 26 (1.32%) hits showed high binding affinity to the recombinant Nsp13 (ΔTm > 3 °C). Among them, seven and four compounds displayed low micromolar inhibitory kinetics on the ATPase (ATP hydrolysis) and helicase (RNA unwinding) activities of Nsp13, respectively. The seven ATPase inhibitors include benidipine (IC50 = 1.07 μM), butylparaben (IC50 = 2.87 μM), diclofenac (IC50 = 6.55 μM), dyclonine HCl (IC50 = 6.54 μM), methyl salicylate (IC50 = 4.53 μM), olsalazine (IC50 = 4.91 μM) and verteporfin (IC50 = 5.01 μM). The four helicase inhibitors include curcumin (IC50 = 12.23 μM), efaproxiral (IC50 = 12.47 μM), fenretinide (IC50 = 13.63 μM) and wedelolactone (IC50 = 14.91 μM). These biochemically validated hits are worth being pursued further for antiviral efficacies and for potential development of leads. The cost-effectively TSA-based HTS strategy can be employed to screen larger compound libraries and adapted to the drug discovery for other protein targets.