In a previous study, the endophytic Bacillus velezensis NC318 was isolated from the rhizosphere of date palm and showed strong antifungal activity against the soil-borne plant pathogenic fungus, Sclerotium rolfsii Sacc, the causal agent of Southern blight. The potential of the Bacillus genus in the inhibition of plant pathogens is mainly due to the production of certain bioactive compounds. In the present study, secondary metabolites extracted from the cell-free supernatant of strain NC318 showed strong antifungal activity on the mycelial growth and germination of S. rolfsii sclerotia in vitro. With 50 μl of bioactive compounds crude extracts, the mycelial growth inhibition rate was 97% and any germination of sclerotia was reported. Chemical analysis of the secondary metabolite crude extracts performed by high performance liquid chromatography coupled with mass spectrometry (HPLC/MS), revealed that the secreted bioactive compounds belonged to the family of lipopeptides (iturin, fengycin, surfactin), polyketides (bacillaene, macrolactin, difficidin and bacilysin) and siderophores (bacillibactin). These results provide a better understanding of the biocontrol mechanism of the bacteria strain B. velezensis NC318 against the soil fungal pathogens, especially S. rolfsii root rot.