Bacterial leaf streak (BLS) of rice is a severe disease caused by the bacterial pathogenXanthomonas oryzaepv.oryzicola(Xoc) that has gradually become the fourth major disease on rice in some rice-growing regions in southern China. Previously, we isolated aBacillus velezensisstrain 504 that exhibited apparent antagonistic activity against theXocwild-type strain RS105, and found thatB. velezensis504 was a potential biocontrol agent for BLS. However, the underlying mechanisms of antagonism and biocontrol are not completely understood. Here we mine the genomic data ofB.velezensis504, and the comparative transcriptomic data ofXocRS105 treated by the cell-free supernatants (CFSs) ofB.velezensis504 to define differentially expressed genes (DEGs). We show thatB.velezensis504 shares over 89% conserved genes with FZB42 and SQR9, two representative model strains ofB.velezensis, but 504 is more closely related to FZB42 than SQR9, as well asB.velezensis504 possesses the secondary metabolite gene clusters encoding the essential anti-Xocagents difficidin and bacilysin. We conclude that approximately 77% ofXocRS105 coding sequences are differentially expressed by the CFSs ofB.velezensis504, which significantly downregulates genes involved in signal transduction, oxidative phosphorylation, transmembrane transport, cell motility, cell division, DNA translation, and five physiological metabolisms, as well as depresses an additional set of virulence-associated genes encoding the type III secretion, type II secretion system, type VI secretion system, type IV pilus, lipopolysaccharides and exopolysaccharides. We also show thatB.velezensis504 is a potential biocontrol agent for bacterial blight of rice exhibiting relative control efficiencies over 70% on two susceptible cultivars, and can efficiently antagonize against some important plant pathogenic fungi includingColletotrichum siamenseandC.australisinensethat are thought to be the two dominant pathogenic species causing leaf anthracnose of rubber tree in Hainan province of China.B.velezensis504 also harbors some characteristics of plant growth-promoting rhizobacterium such as secreting protease and siderophore, and stimulating plant growth. This study reveals the potential biocontrol mechanisms ofB.velezensisagainst BLS, and also suggests thatB.velezensis504 is a versatile plant probiotic bacterium.