Human noroviruses (HuNoVs) are a major cause of epidemic and sporadic cases of acute gastroenteritis worldwide. Recently, human intestinal enteroids (HIEs) have been shown to support the replication of HuNoVs, and be an excellent model to study HuNoV-host interactions. We implemented the HIE system in our laboratory and investigated the global molecular events associated with the mechanism of HuNoV-host interactions. Successful replication was observed for several norovirus GII genotypes, and totally 5,376 genes with different expression in HIEs were identified during infection. Bioinformatics analysis revealed that several important pathways, especially the "Signal transduction" and "Immune system" pathways, were involved in the HuNoV-host interaction. Quantitative PCR results validated that IFN-λ instead of IFN-β was elevated in HIEs after infection. Our study showed the holistic understanding of the transcriptome events in the HIE model infected by HuNoVs, and highlighted the important role of IFN-λ signaling in the HuNoV-host interactions.