E166V in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nsp5 protease confers strong resistance to the antiviral component of Paxlovid, nirmatrelvir (NIR), in passaging and clinical samples. In SARS-CoV-2 replicons, E166V drastically decreased Washington (WA1) but not Omicron (BA.1) fitness (20- versus 2-fold), suggesting a lower barrier to resistance in the BA.1 strain and consistent with observed differences in respective nsp5 dimerization affinities. Crystal structures reveal a steric clash between the rigid, bulky NIR tert -butyl group and the β-branched Val 166 , disrupting the covalent binding of NIR to the catalytic Cys 145 and leading to high resistance in BA.1 and WA1 replicons. NIR-resistant replicons remained susceptible to GC376, which can still covalently bind Cys 145 by avoiding a steric clash with Val 166 through “wiggling and jiggling.” Hence, strategic flexibility is a strategy that will help design second-generation antivirals against NIR-resistant viruses.