Rice blast disease caused by the filamentous Ascomycetous fungus Magnaporthe oryzae is a major threat to rice production worldwide. The mechanisms underlying rice resistance to M. oryzae, such as transcriptional reprogramming and signaling networks, remain elusive. In this study, we carried out an in-depth comparative transcriptome study on the susceptible and resistant rice cultivar in response to M. oryzae. Our analysis highlighted that a rapid, high-amplitude transcriptional reprogramming was important for rice defense against blast fungus. The ribosome- and protein translation-related genes were significantly enriched in differentially expressed genes (DEGs) at 12 hpi in both cultivars, indicating that the protein translation machinery is regulated in the activation of immunity in rice. Furthermore, we identified a core set of genes that are involved in the rice response to biotic as well as to abiotic stress. More importantly, among the core genes, we demonstrated that the metallothionein OsMT1a and OsMT1b genes positively while a peroxidase gene Perox4 negatively regulated rice resistance to M. oryzae. Our study provides novel insight into transcriptional reprogramming and a valuable resource for functional studies on rice immune signaling components in resistance to blast disease.