Bacterial wilt, caused by the Ralstonia solanacearum, can infect several economically important crops. However, the management strategies available to control this disease are limited. Plant growth-promoting rhizobacteria (PGPR) have been considered promising biocontrol agents. In this study, Bacillus amyloliquefaciens strain Cas02 was isolated from the rhizosphere soil of healthy tobacco plants and evaluated for its effect on plant growth promotion and bacterial wilt suppression. Strain Cas02 exhibited several growth-promoting-related features including siderophore production, cellulase activity, protease activity, ammonia production and catalase activity. Moreover, strain Cas02 showed a significant inhibitory growth effect on R. solanacearum, and its active substances were separated and identified to be macrolactin A and macrolactin W by HPLC-DAD-ESI-MS/MS. Both greenhouse and field experiments demonstrated a good performance of Cas02 in plant growth promotion and bacterial wilt suppression. To explore the underlying genetic mechanisms, complete genome sequencing was performed and the gene clusters responsible for antibacterial metabolites expression were identified. Overall, these findings suggest that the strain Cas02 could be a potential biocontrol agent in bacterial wilt management and a source of antimicrobial compounds for further exploitation.