Objective To analyze the transcriptome data of Zika virus (ZIKV)-infected human neuroblastoma cells SH-SY5Y by bioinformatics method, and to identify the potential genes involved in the pathogenic mechanism of ZIKV. Methods SH-SY5Y cells were infected with ZIKV.The total RNA was extracted and the differentially expressed genes (DEGs) were screened by transcriptome sequencing.Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict the biological processes, molecular functions, and signaling pathways mainly involved in the DEGs, and the results were verified by quantitative polymerase chain reaction (qPCR). Results A total of 259 DEGs were identified, including 172 up-regulated genes and 87 down-regulated genes.GO functional enrichment analysis showed that the DEGs were mainly related to extracellular matrix, response to stimulus, antimicrobial humoral response, and developmental process.KEGG pathway enrichment analysis revealed that the DEGs were predominantly associated to inflammatory reaction and immune response.The qPCR validation results of DEGs were basically consistent with the transcriptome sequencing results. Conclusion The expression of genes involved in extracellular matrix, response to stimulus, and regulation of inflammatory reaction is significantly altered in SH-SY5Y cells after ZIKV infection, suggesting that ZIKV may cause neurological lesions by remodeling the extracellular matrix and regulating inflammatory reaction.