Significance Host innate immune responses are the first line of defense against viral infections, with the outcome of infection determined by the interplay between virus and host defense mechanisms. We report transcriptomic and functional analyses of epithelial cell responses to HuNoV infection in HIE cultures. HuNoV infection triggers predominantly a type III interferon (IFN) response and upregulation of long noncoding RNAs. Exogenously added IFNs restrict HuNoV replication in a strain-independent manner, but we unexpectedly found strain-dependent effects of endogenously activated cellular IFNs. Our findings suggest strain-specific sensitivities to IFN as a factor for global dominance of pandemic strains, provide a new arsenal of stable HIE knockout lines for several IFN pathways, and highlight strain differences as a consideration for development of effective therapies.