The development of effective antibacterial agents equipped with novel action modes and unique skeletons starting from natural compounds serves as an important strategy in the modern pesticide industry. Disclosed here are a series of novel indole derivatives containing pyridinium moieties and their antibacterial activity evaluation against two prevalent phytopathogenic bacteria, Xanthomonas oryzae pv. oryzicola (Xoc) and X. oryzae pv. oryzae (Xoo). A three-dimensional (3D)-QSAR model was adopted to discover higher activity like title compounds based on the Xoc antibacterial activity of the tested compounds. Compound 43 was consequently designed, and it displayed higher antibacterial activity as expected with the half-maximal effective concentration EC50 values of 1.0 and 1.9 μg/mL for Xoo and Xoc, respectively, which were better than those of the commercial drug thiodiazole copper (TC) (72.9 and 87.5 μg/mL). Under greenhouse conditions, the results of a rice in vivo pot experiment indicated that the protective and curative activities of compound 43 against rice bacterial leaf streak (BLS) and rice bacterial blight (BLB) were 45.0 and 44.0% and 42.0 and 39.3%, respectively, which were better than those of the commercial agent thiodiazole copper (38.0 and 37.9%, 38.6 and 37.0%) as well. Scanning electron microscopy images, defense enzyme activity tests, and proteomic techniques were utilized in a preliminary mechanism study, suggesting that compound 43 shall modulate and interfere with the physiological processes and functions of pathogenic bacteria.