Ornithodoros moubata serves as primary vector of African swine fever and tick-borne human relapsing fever in Africa. Developing an effective vaccine targeting this argasid tick would significantly enhance disease control measures. To identify potential vaccine targets, the recently characterised sialome of O. moubata was analysed using a vaccinomics approach. This led to the identification of a set of salivary secreted proteins predicted to be antigenic and implicated in the regulation of blood-feeding and host immune defences. The objective of this study was to evaluate the protective potential of seven of these proteins, namely Complement inhibitor (OmCI), Cyclophilin (OmCPH), Hypothetical protein 275 (OmH275), Peroxiredoxin (OmPXR), Calreticulin (OmCLR), Neprilysin (OmNEP), and Superoxide dismutase (OmSOD). These candidates were produced as recombinant proteins, formulated with Montanide adjuvant, and administered individually to different groups of rabbits. Adult and nymphal-3 specimens of O. moubata and Ornithodoros erraticus (the Mediterranean vector of ASF and TBRF) were allowed to feed on the vaccinated rabbits, and the ticks’ feeding performance, survival, and reproduction rates were assessed. OmH275, OmPXR, OmCPH, and OmCLR conferred 20 %–32 % protection against O. moubata and/or O. erraticus, whereas OmCI, OmNEP, and OmSOD afforded 2 %–17 % protection against one or both tick species. Consequently, OmH275, OmPXR, OmCPH, and OmCLR were deemed suitable candidates for inclusion in the development of anti-Ornithodoros cocktail vaccines, while OmCI, OmNEP, and OmSOD were considered less promising for tick vaccine development. These findings validate the vaccinomics pipeline, identifying four of seven candidates (57 %) as viable antigens for Ornithodoros tick vaccines.