Rice blast, caused by Pyricularia oryzae, is one of the most destructive diseases in agriculture, leading to severe impacts on rice crop harvests worldwide. CRISPR/Cas9 system has proven to be an effective tool for functional genomics revealing several host plant susceptibility genes as an attractive source for building plant resistance, thus contributing to rice improvement. In a previous study, we showed that rice genes OsDjA2 and OsERF104, encoding a chaperone protein and an APETELA2/ethylene-responsive factor, respectively, were strongly induced in a compatible interaction with blast fungus, and had also their function in plant susceptibility validated via gene silencing. In the present study, we aimed at generating rice-blast resistant plants through the knockout of the revealed rice susceptibility genes by the usage of CRISPR/Cas9 technology. T-DNA binary vector constructs were used to transform mature seed embryo-derived calli of rice cv. Nipponbare by Agrobacterium-mediated genetic transformation. We obtained 24 primary transformant (T0) plants for each targeted gene. A total of 23 (95.83%) T0 recovered plants of both OsDjA2 and OsERF104 were T-DNA PCR positive. The screening for T-DNA copy number integrated into their genomes by qPCR revealed fifteen (62.5%) OsDjA2 and seventeen (70.83%) OsERF104 primary transformant plants containing only 1-2 transgene copies, which were selected for further Sanger sequencing. Among OsDjA2 targeted alleles, there were 8 (57%) harboring bi-allelic mutations, 5 (36%) homozygous, and 1 (7%) heterozygous. Likewise, among OsERF104 mutant lines there were 5 (41%) harboring bi-allelic mutations, 6 (50%) homozygous, and 1 (8%) heterozygous. T1 homozygous edited plants harboring loss-of-function predicted mutations were tested for disease resistance. The phenotyping revealed not only a significant decrease in the number of blast lesions but also a reduction in the percentage of diseased leaf area, compared with the wild-type infected control plants. Our results support CRISPR/Cas9-mediated target mutation in rice susceptibility genes as a potential and alternative breeding strategy for building resistance to blast disease.