Protein ubiquitination is crucial for the host cellular response to influenza A virus (IAV) infections. Monocytes, key players of the innate immune response, are susceptible to IAV infections and produce proinflammatory cytokines. However, the role of global ubiquitination in IAV-infected monocytes is unknown. Here, by using comprehensive proteomics analysis, we unveiled a robust upregulation of global protein ubiquitination in monocytes during early IAV infection, which declined at later stage. Unlike its traditional proteolytic role, this virus-induced ubiquitination is non-proteolytic and regulates cytosolic-to-nuclear protein localization. By artificially sequestering cellular free ubiquitin to interfere with ubiquitination during influenza infection in monocytes, we demonstrated that this ubiquitination increase is anti-inflammatory by dampening TNF-α production. By examining the most highly ubiquitinated protein, COA7, we learned that IAV induced ubiquitination leads to the translocation of COA7 from mitochondria to the nucleus, concomitant with binding to the RNA processing machinery and repression of TNF-α expression as well as of viral RNA induced stress granules formation. In summary, infection of monocytes by IAV trigger a global increase in non-proteolytic protein ubiquitination, which regulates protein nuclear localisation and suppresses proinflammatory TNF-a expression. These results identify a novel mechanism by which monocytes counteract excessive inflammation during IAV infection.