Dengue virus (DENV) infection is a major global public health concern, and there is no effective vaccine for it. In this study, we describe the design and characterization of three nucleotide-modified mRNA vaccines (prME-mRNA, E80-mRNA, and NS1-mRNA) for DENV-2. Our results showed that vaccination with E80-mRNA alone or a combination of E80-mRNA and NS1-mRNA can induce high levels of neutralizing antibodies and antigen-specific T cell responses; furthermore, these vaccines confer complete protection against DENV-2 challenge in immunocompetent mice. These data provide foundations for further development of a tetravalent DENV vaccine based on nucleotide-modified mRNA.