Since the discovery of penicillin, bacteria are known to be major sources of secondary metabolites that can function as drugs or pesticides. Scientists worldwide attempted to isolate novel compounds from microorganisms; however, only less than 1% of all existing microorganisms have been successfully identified or characterized till now. Despite the limitations and gaps in knowledge, in recent years, many Bacillus velezensis isolates were identified to harbor a large number of biosynthetic gene clusters encoding gene products for the production of secondary metabolites. These chemically diverse bioactive metabolites could serve as a repository for novel drug discovery. More specifically, current projects on whole-genome sequencing of B. velezensis identified a large number of biosynthetic gene clusters that encode enzymes for the synthesis of numerous antimicrobial compounds, including lipopeptides and polyketides; nevertheless, their biological applications are yet to be identified or established. In this review, we discuss the recent research on synthesis of bioactive compounds by B. velezensis and related Bacillus species, their chemical structures, bioactive gene clusters of interest, as well as their biological applications for effective plant disease management.