To discover novel antibacterial agents, a series of novel 1,3,4-thiadiazole derivatives containing an amide moiety were designed and synthesized, and their antibacterial activities were tested. Compound 30 was designed and synthesized according to the CoMFA model. Compound 30 exhibited higher antibacterial activities against Xanthomonas oryzae pv. oryzicola and Xanthomonas oryzae pv. oryzae, with EC50 values of 2.1 and 1.8 mg/L, respectively, which were superior to those of thiodiazole copper (99.6 and 92.5 mg/L). The protective and curative activities of compound 30 against rice bacterial leaf blight were 51.3 and 46.1%, respectively, which were better than those of thiodiazole copper (37.8 and 38.5%). The protective and curative activities of compound 30 against rice bacterial leaf streak were 45.9 and 40.5%, respectively, which were better than those of thiodiazole copper (36.2 and 31.1%). In addition, the protective activity of compound 30 against rice bacterial leaf streak was related to increased activities of related defense enzymes and upregulated the differentially expressed proteins of the glycolysis/gluconeogenesis pathway.