Exposure to microgravity has become the primary factor threatening astronauts' health. Immunity is dysregulated rapidly following spaceflight, and reactivation of latent virus has been observed. However, systematic studies and molecular mechanisms of the adverse impact of microgravity on the antiviral immune response are still elusive. As a member of the Tetraspanins family, CD82 participates in the biological process between the cell and the trafficking of cellular transmembrane proteins that interact with many viruses. Herein, we established a ground-based zebrafish model of microgravity to research the embryogenesis processes under space microgravity. In this study, we cloned and validated the open reading frame (ORF) sequence of CD82 homolog and explored the expression profile of CD82 homolog in various zebrafish tissues. Overexpression of zebrafish CD82a increased host IFN1 and vig1 transcription during the spring viremia of carp virus (SVCV) infection. Furthermore, a significant down-regulation of gene expression, including IFN1 and vig1, caused by knockdown of CD82a was observed. Additionally, the knockdown of CD82a significantly upregulated the SVCV replication in the EPC cells. Accordingly, CD82a positively indued the cellular antiviral responses triggered by the SVCV. Moreover, the mRNA level of CD82 homolog was upregulated in vivo and in vitro under simulated microgravity. Collectively, our studies further implied that the high expression of CD82a could modulate innate antiviral immunity in an IFN-independent manner during microgravity conditions.