The plant intracellular Ras-group related leucine-rich repeat proteins (PIRLs) play important roles in pollen tube growth and development. However, the role of PIRLs in modulating defense responses against fungal diseases has not been reported. In this study, the IbPIRL8 gene was isolated from the resistant variety Nongdabai. Its expression was strongly induced by salicylic acid (SA) and methyl jasmonate. The IbPIRL8 protein was localized to the nucleus and cell membrane. Overexpression of IbPIRL8 conferred resistance to soft rot and root rot in sweet potato. Key SA-responsive genes, cellulose biosynthesis-related genes and callose biosynthesis-related genes were upregulated in IbPIRL8-OE plants compared with wild type (WT). Consistently, the storage roots of IbPIRL8-OE plants accumulated more endogenous SA, cellulose and callose than WT plants. Yeast one-hybrid, dual-luciferase, and electrophoretic mobility shift assays demonstrated that IbDEAR2, induced by Rhizopus stolonifer, binds to the IbPIRL8 promoter to repress its expression. These findings provide insights into the genetic basis for improving disease-resistant sweet potato varieties.