The agonists of toll-like receptor 9, synthetic oligodeoxynucleotides (ODNs) containing CpG sequences, stimulate innate and adaptive immune responses in humans and a variety of animal species. The aim of this study was to evaluate the immunomodulatory effects of four types of CpG ODNs as potential porcine vaccine adjuvants. In this study, four classes of swine CpG ODNs with distinct structural and biological properties were designed. Their abilities to trigger the expression of TLRs, antigen-presenting molecules and cytokines and to induce antiviral effects were determined in three different types of porcine cells (IPEC-J2, peripheral blood mononuclear cells (PBMCs), and 3D4/21). Our results showed that the four CpG ODNs triggered various types of molecular expression changed at the level of transcription. They activated the cytosolic antivirus TLRs at different levels, altered the mRNA expression of antigen-presenting molecules and intracellular signal transduction molecules, and triggered mRNA of cytokine production in a CpG type-specific and cell-specific manner at CpG ODNs, with the exception of type D, significantly increased IFN-α, IFN-β and TNF-α production and induced efficient anti-viral effects in IPEC-J2 cells but had little effect on MHC I expression. The designed CpG ODNs are useful for promoting early innate immunity and mucosal immunity and may also be promising adjuvant candidates for the treatment of porcine infectious diseases.