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Infectious respiratory diseases caused by <i>Bordetella bronchiseptica</i> (<i>Bb</i>) are seriously endangering the development of the rabbit industry in China. Unfortunately, no licensed vaccines are available for this pathogen. The present study was designed to determine whether the inactivated <i>Bb</i> antigen formulated with vegetable oil adjuvant (named E515) which contains soybean oil, vitamin E, and ginseng saponins, functions as a safe and effective vaccine (E515-<i>Bb</i>) against <i>Bb</i> infection in rabbits. Based on local and systemic reactions, both the E515 adjuvant alone and the E515-<i>Bb</i> vaccine exhibited good safety in rabbits. Immune response analysis implies that rabbits immunized with the E515-<i>Bb</i> vaccine produced significantly higher, earlier, and longer-lasting specific antibody responses and activated Th1/Th2/Th17 cell responses than those immunized with the aluminum hydroxide (Alum)-adjuvanted <i>Bb</i> vaccine (Alum-<i>Bb</i>) or <i>Bb</i> antigen alone. Moreover, the E515-<i>Bb</i> vaccine effectively protected rabbits from <i>Bb</i> infection. Additionally, integrated multi-omics analysis revealed that the immunoprotective effect of the E515-<i>Bb</i> vaccine was achieved through upregulation of the complement and coagulation cascades and cell adhesion molecule (CAM) pathways, and the downregulation of the P53 pathway. Overall, these results indicate that the E515-<i>Bb</i> vaccine is safe, elicits an efficient immune response and provides good protection against <i>Bb</i> infection in rabbits. Thus, the E515-adjuvanted <i>Bb</i> vaccine can be considered a promising candidate vaccine for preventing <i>Bb</i> infection.