Rice ARGONAUTE2 (OsAGO2) is a core component of the rice RNA-induced silencing complex (RISC), which is repressed by Magnaporthe oryzae (M. oryzae) infection. Whether and how OsAGO2-mediated gene silencing plays a role in rice blast resistance and which sRNAs participate in this process are unknown. Our results indicate that OsAGO2 is a key immune player that manipulates rice defense responses against blast disease. OsAGO2 associates with the 24-nt miR1875 and binds to the promoter region of HEXOKINASE1 (OsHXK1), which causes DNA methylation and leads to gene silencing. Our multiple genetic evidence showed that, without M. oryzae infection, OsAGO2/miR1875 RISC promoted OsHXK1 promoter DNA methylation and OsHXK1 silencing; after M. oryzae infection, the reduced OsAGO2/miR1875 led to a relatively activated OsHXK1 expression. OsHXK1 acts as a positive regulator of blast disease resistance that OsHXK1-OE rice exhibited enhanced resistance, whereas Cas9-Oshxk1 rice showed reduced resistance against M. oryzae infection. OsHXK1 may function through its sugar sensor activity as glucose induced defense-related gene expression and reactive oxygen species (ROS) accumulation in Nipponbare and OsHXK1-OE but not in Cas9-Oshxk1 rice. OsAGO2 itself is delicately regulated by OsPRMT5, which senses M. oryzae infection and attenuates OsAGO2-mediated gene silencing through OsAGO2 arginine methylation. Our study reveals an OsPRMT5-OsAGO2/miR1875-OsHXK1 regulatory module that fine tunes the rice defense response to blast disease.