<p>SARS-CoV-2 is now endemic, with infections commonplace. While much of the population now has immunity, some subsets remain at risk. For such individuals, small-molecule antivirals are the frontline treatment. However, studies have identified resistance-conferring mutations to these compounds, and there are now cases of resistant viruses emerging during treatment. These occurrences make clear the need to understand the resistance mechanisms for SARS-CoV-2 antivirals. Here, we report the pathways to resistance for atilotrelvir and simnotrelvir, two 3CL protease inhibitors used for COVID-19 treatment, and ibuzatrelvir, a compound in late-stage clinical development. Through high-throughput passaging, we reveal that resistance can readily arise, and that there is a large degree of overlap in the mutations which emerge. Moreover, viral inhibition assays demonstrate that there is not only strong cross-resistance between the emerged viruses against these three molecules, but also against two additional widely used antivirals, nirmatrelvir and ensitrelvir, as well. Cellular assays highlight S144A, E166A, and E166V as mediating broad resistance, with E166V having the strongest effects. These results have important clinical implications, including the need to carefully consider cross-resistance properties in salvage therapy and combination treatment, as well as emphasizing the need for the further development of SARS-CoV-2 antivirals with differing modalities.</p>