Natural rubber is an indispensable material of strategic importance that has critical applications in industry and the military. However, the development of the natural rubber industry is impeded by the red root rot disease of rubber trees caused by Ganoderma pseudoferreum, which is one of the most devastating diseases in the rubber tree growing regions in China. To combat this disease, we screened the antifungal activity of 223 candidate bacterial strains against G. pseudoferreum, and found that Bacillus velezensis strain SF305 exhibited significant antifungal activity against G. pseudoferreum. B. velezensis SF305 had a nearly 70% efficacy against the red root rot disease of rubber trees with the therapeutic treatment (Tre), while it exhibited over 90% protection effectiveness with the preventive treatment (Pre). The underlying biocontrol mechanism revealed that B. velezensis SF305 could reduce the disease severity of red root rot by degrading the mycelia of G. pseudoferreum. An antiSMASH analysis revealed that B. velezensis SF305 contains 15 gene clusters related to secondary metabolite synthesis, 13 of which are conserved in species of B. velezensis, but surprisingly, B. velezensis SF305 possesses 2 unique secondary metabolite gene clusters. One is predicted to synthesize locillomycin, and the other is a novel nonribosomal peptides synthetase (NRPS) gene cluster. Genomic analysis showed that B. velezensis SF305 harbors genes involved in motility, chemotaxis, biofilm formation, stress resistance, volatile organic compounds (VOCs) and synthesis of the auxin indole-3-acetic acid (IAA), suggesting its plant growth-promoting rhizobacteria (PGPR) properties. B. velezensis SF305 can promote plant growth and efficiently antagonize some important phytopathogenic fungi and bacteria. This study indicates that B. velezensis SF305 is a versatile plant probiotic bacterium. To the best of our knowledge, this is the first time a B. velezensis strain has been reported as a promising biocontrol agent against the red root rot disease of rubber trees.