To ensure the production of food crops, a series of cryptolepine derivatives were synthesised, after which their antibacterial activities and mechanism of action against three plant pathogens were investigated. Our bioassay results indicated that most of the target compounds displayed potent inhibitory effects against Xanthomonas oryzae (X. oryzae) and Xanthomonas axonopodis pv. citri (X. axonopodis pv. c.). Remarkably, compound 9 exhibited the best in vitro antibacterial activity against X. oryzae, with a minimum inhibitory concentration (MIC) value of 0.78 μg·mL^–1. Compound 2 exhibited the best in vitro antibacterial activity against X. axonopodis pv. c., with an MIC value of 0.39 μg·mL^–1. These activities were superior to those of copper quinolate (MIC = 6.25, 25 μg·mL^–1) and thiodiazole copper (MIC = 100, 200 μg·mL^–1) against X. oryzae and X. axonopodis pv. c. In vivo experiments demonstrated the promising applicability of compound 9 for the control of rice bacterial infections. Furthermore, compound 9 was selected as a candidate to conduct preliminary analyses of the antibacterial mechanisms of cryptolepine derivatives. Scanning electron microscopy and transmission electron microscopy observations, extracellular polysaccharide production, biofilm formation, transcriptomic, quantitative reverse transcription-polymerase chain reaction analyses, and molecular docking assays were performed. Collectively, our findings demonstrated that compound 9 might act via multifarious mechanisms to down-regulate virulence factors and cause cell death.