In the current study, gene network analysis revealed five novel disease-resistance proteins against bacterial leaf blight (BB) and rice blast (RB) diseases caused by Xanthomonas oryzae pv. oryzae (Xoo) and Magnaporthe oryzae (M. oryzae), respectively. In silico modeling, refinement, and model quality assessment were performed to predict the best structures of these five proteins and submitted to ModelArchive for future use. An in-silico annotation indicated that the five proteins functioned in signal transduction pathways as kinases, phospholipases, transcription factors, and DNA-modifying enzymes. The proteins were localized in the nucleus and plasma membrane. Phylogenetic analysis showed the evolutionary relation of the five proteins with disease-resistance proteins (XA21, OsTRX1, PLD, and HKD-motif-containing proteins). This indicates similar disease-resistant properties between five unknown proteins and their evolutionary-related proteins. Furthermore, gene expression profiling of these proteins using public microarray data showed their differential expression under Xoo and M. oryzae infection. This study provides an insight into developing disease-resistant rice varieties by predicting novel candidate resistance proteins, which will assist rice breeders in improving crop yield to address future food security through molecular breeding and biotechnology.