Diseases caused by Phytophthora species seriously affect global crop production and food security. Identification of key factors involved in plant resistance is valuable for disease management. Previously, we characterized the transcriptome of Nicotiana benthamiana which was infected with Phytophthora parasitica. Here, we selected NbERF173, one of the most strongly up-regulated genes of N. benthamiana in response to P. parasitica infection, for further investigation. First, NbERF173 encodes a conserved transcription factor in our tested plant species. Second, overexpression of NbERF173in N. benthamiana enhanced its resistance to P. parasitica, and silencing of NbERF173 significantly promoted the infection of both P. parasitica and Botrytis cinerea. Additionally, we demonstrated that NbERF173 can participate in reprograming of gene expression during P. parasiticainfection and manipulate expression patterns of many defense-related genes, including two proteinase inhibitors encoding genes (PI1-B and KTI1). Furthermore, overexpression of PI1-Band KTI1 strengthened plant resistance to P. parasitica and partially restored the deficiency in resistance of NbERF173-silenced N. benthamiana plants. Finally, we found that NbERF173 could not bind to the promoters of PI1-B and KTI1using yeast one-hybrid assay. Together, our results suggest that NbERF173 positively regulate the disease resistance, probably by reprograming of defense-related genes.