Babesiosis is caused by a genus of tick-transmitted apicomplexan parasites with considerable economic, medical, and veterinary impact. Bovine babesiosis is an important impediment to livestock production throughout the world. Limited options are available for control of this widespread protozoal disease. This study evaluated the protective effect of DNA vaccines incorporating Babesia cysteine proteases and Apical Membrane Antigen-1 separately and in combination. The Helios Gene Gun System was used to vaccinate BALB/c mice with plasmid DNA constructs encoding different B. microti proteins (pBmCP1, pBmAMA1 or a combination of pBmCP1 and pBmAMA1). An analysis of the parasitemia post-challenge supports the hypothesis that pBmCP1 and pBmAMA1 induce protective effects against the progression of the parasite. However, the combination of the two constructs given simultaneously has no marked effect on parasite progression. Furthermore, the data obtained from the packed cell volumes of the mice indicates that only BmCP1 is able to reduce this effect of clinical disease with any level of significance. Babesia bovis constructs containing Cysteine Protease-2 and Apical Membrane Antigen-1 were created and sequence verified for use in future vaccination studies. The results seen using the mouse model of Babesiosis may provide applicable information for the design of vaccines against other Babesia spp., particularly for B. bovis.