Sacbrood virus (SBV), which infects honey bee larvae and causes significant mortality, represents a serious threat to bee populations and the beekeeping industry. SBV affects both Apis mellifera and Apis cerana, designated according to the host and genotype (AmSBV-AM and AcSBV-AC); however, A. cerana experiences higher mortality rates compared to A. mellifera. Additionally, cross-infections have been observed in both bee species. The genetic regulatory mechanisms involved in infected larvae remain largely unexplored. This study aims to investigate the molecular differences in the responses of A. cerana infected with AcSBV-AC and A. mellifera infected with AmSBV-AM. The results demonstrated significant differences in the expression patterns of differentially expressed genes (DEGs) between the two bee species. Gene Ontology (GO) analysis revealed that, at 24 h post-infection (h.p.i.), A. cerana/AcSBV-AC group exhibited a greater number of downregulated DEGs compared to A. mellifera/AmSBV-AM group, with many of these DEGs being associated with insect development. Furthermore, RT‒qPCR validation indicated that the genes RPA2 and MUS81 are potentially involved in SBV replication and host-virus specificity in both species. The development-related genes, Dpp and Yellow-f, showed downregulation, it may contribute to the increased susceptibility of A. cerana larvae to SBVs. Notably, following dsRNA treatment, the core genes Dpp, Yellow-f, RPA2, and Pyruva in A. cerana/AcSBV-AC group exhibited an inverse regulation trend, indicating that inhibiting AcSBV-AC can reverse the host core genes expression patterns and potentially enhance larval survival rates. Based on the above, these core genes may play a crucial role in SBV infection of A. cerana larvae.