SARS-CoV-2 NSP14 exonuclease (ExoN) activity is critical for viral replication fidelity and therefore represents an attractive antiviral target. Drug discovery for nucleases such as NSP14 is challenging due to the lack of suitable high-throughput assay methodologies. Here, a SAMDI-MS assay was optimized for NSP14 ExoN and miniaturized, achieving Z factors > 0.8 and signal-to-background ratios > 200. Next, we screened ~140,000 drug-like compounds to reveal candidate inhibitors. The hits were validated and assessed for selectivity and RNA intercalation. The compounds represent some of the first NSP14 ExoN inhibitors and offer new avenues to combat COVID-19 and other coronavirus infections.