Caseous lymphadenitis (CLA) is a chronic disease that affects sheep and goats worldwide and causes significant economic losses, and the best strategy to reduce clinical cases is vaccination. This study evaluated the immune response and protection rates of the Corynebacterium pseudotuberculosis-derived ascorbate transporter subunit (rPTS) and Ribonuclease protein (rRBN) recombinant proteins in mice and goats. Groups of eight Swiss mice each were inoculated with rPTS + Al(OH) (G1), rPTS + Saponin (G2), rRBN + Al(OH) (G3), rRBN + Saponin (G4), rPTS + rRBN + rCP40 + Al(OH) (G5), rPTS + rRBN + rCP40 + Saponin (G6), Control Al(OH) (G7) and Control Saponin (G8), respectively. The mice received two vaccine doses and were challenged with a virulent C. pseudotuberculosis strain. In addition, five groups of eight goats each were inoculated with sterile saline (G1), rPTS (G2), rRBN (G3), rCP40 (G4), and rPTS + rRBN + CP40 (G5), associated with saponin. ELISAs was used to detect specific total IgG in mice and goats, and the goat specific IFN-γ production was quantified. All immunized mice presented a peak of specific total IgG on day 60, and a higher survival rate (75%) was achieved in animals immunized with a pool of the recombinant proteins associated with saponin. Also, goats immunized with the same formulation produced significant levels of specific antibodies from day 15 post immunization and were able to significantly produce specific IFN-γ at 90 days post-immunization. Our findings suggest that the formulation containing the association of the proteins rPTS, rRBN and rCP40 associated to saponin adjuvant resulted in the best protection against the challenge in mice and was able to elicit an IFN-γ-characterized Th1 immune response in goats, and can be considered as a promising vaccine formulation for CLA.