Powdery mildew caused by Erysiphe lonicerae var. lonicerae is a serious disease that causes significant loss to honeysuckle production in China. This disease is difficult to control by chemical measures, thus biological control may constitute a powerful alternative strategy. To develop an environmentally friendly microbial agent for biocontrol of powdery mildew, we screened strains of Bacillus spp. for biocontrol potential. One of the 102 isolates, strain HC-8, demonstrated high antifungal activity against three phytopathogenic fungi and efficiently suppressed the conidia germination of E. lonicerae under in vitro conditions. This isolate, which offered significant biocontrol of powdery mildew disease in honeysuckle, was identified as belonging to Bacillus velezensis. After challenge inoculation with E. lonicerae, honeysuckle plants treated with a concentration of 1 × 108 CFU/ml showed the highest protection value (PV). Biocontrol efficacy was highest when strain HC-8 was applied prior to pathogen inoculation, and the minimum PV was recorded when HC-8 was used 1 day after pathogen inoculation. Populations of the GFP-tagged strain HC-8-gfp persisted on honeysuckle leaves up to 25 days after spraying. In addition, we found that B. velezensis HC-8 induced defense-related enzyme activities in the leaves of honeysuckle. Thus, the present study provides a potential high-efficiency strategy for the biological control of powdery mildew disease and shows that B. velezensis HC-8 has significant potential as a biocontrol agent for honeysuckle production.