Chikungunya virus (CHIKV) is an important arthritogenic human pathogen that is already circulating in both hemispheres. In the present study, we substituted VLoop, located on the surface of nsP2, by other amino acid sequences. These modifications had deleterious effects on viral nuclear functions and made CHIKV incapable of interfering with the induction of type I interferon and the antiviral response in both mouse and human cells. Importantly, the identified mutations have no significant effects on the synthesis of virus-specific RNAs and viral structural proteins. The designed mutants induced a few orders of magnitude lower viremia but remained highly immunogenic in mice. Thus, the proposed modifications of nsP2 can additionally improve the safety of the attenuated strain CHIKV 181/25. Furthermore, defined mutations in the macro domain of another nonstructural protein, nsP3, additionally reduce cytopathogenicity of nsP2 mutants in human cells, and can be potentially applied for CHIKV attenuation.