T cell SERINC proteins were recently identified as human immunodeficiency virus (HIV) restriction factors that diminish viral infectivity by incorporation into virions. Here we provide evidence that SERINC3 and SERINC5 perform additional antiviral activity by enhancing the type I interferon (IFN-I) and NF-κB signaling pathways. SERINC5 interacts with the mitochondrial antiviral-signaling (MAVS) and TRAF6 proteins, resulting in MAVS aggregation and TRAF6 polyubiquitination. Knockdown of SERINC5 in the target cell increases single-round HIV-1 infectivity, as well as infection by recombinant vesicular stomatitis virus (rVSV) bearing VSV-G or Ebola virus (EBOV) glycoprotein (GP). Infection by an endemic Asian strain of Zika virus (ZIKV) FSS13025 is also enhanced by SERINC5 knockdown, suggesting that SERINC5 has direct antiviral activity. Further experiments indicated that the antiviral activity of SERINC5 is IFN-I dependent. Altogether, our work uncovered a new function of SERINC proteins that promotes IFN-I and NF-B inflammatory signaling, thus contributing to SERINC-mediated antiviral activity.