The resistance of Castanea mollissima Shuhe-WYL strain to Dryocosmus kuriphilus and its molecular mechanism were examined. The larvae of D. kuriphilus were inoculated on the Shuhe-WYL and Qingzha strains, and mortality was observed and compared; the relative mRNA content of the OsCDPK2, receptor-like protein, OsNAC6 protein, KH domain protein, RNA-binding protein, and the bHLH genes was detected using real-time polymerase chain reaction, and then compared between the Shuhe-WYL and Qingzha strains. Phenylalanine ammonia-lyase content was detected by western blotting and compared between the inoculated Shuhe-WYL, non-inoculated Shuhe-WYL, and inoculated Qingzha strains. The mortalities of larvae inoculated on the bud, bracteal leaf, and cardiac lobe were lower in Shuhe-WYL than Qingzha at 48 and 96 h after inoculation; the contents of OsCDPK2, receptor-like protein, OsNAC6 protein, and bHLH in the cardiac lobe were higher in Shuhe-WYL than in Qingzha at 96 h after inoculation, but KH domain protein and RNA-binding protein were not significantly different. The content of phenylalanine ammonia-lyase in the cardiac lobe was higher in inoculated and non-inoculated Shuhe-WYL compared to inoculated Qingzha at 15, 30, 45, and 60 days, and higher in inoculated Shuhe-WYL than in non-inoculated Shuhe-WYL at 15, 30, 45, and 60 days. The content of phenylalanine ammonia-lyase in the cardiac lobe of inoculated Shuhe-WYL had no significant difference between at 60 and at 45 days; and was higher at 60 and 45 days than at 30 and 15 days; and was higher at 30 days than at 15 days (60≈45˃30˃15 days). The C. mollissima Shuhe-WYL strain was resistant to D. kuriphilus; high expression of OsCDPK2, receptor-like protein, OsNAC6 protein, and bHLH and phenylalanine ammonia-lyase may explain the mechanism.