Influenza virus nucleoprotein (NP) plays critical roles in viral RNA packaging and replication, a process that relies on the dynamic equilibrium between its monomeric and polymeric states. However, the regulatory mechanisms of NP’s function and fate are largely unknown. Here, we employed an RdRp/vRNP-targeted method, discovered that the cellular protein phosphatase PPM1G is a phosphatase of NP and required for maintaining viral replication. In ppm1gflox/flox-Sftpc Cre mice, lethal influenza infection led to survival and mild disease, as well as reduced lung viral loads and inflammation. PPM1G expression is upregulated upon influenza virus infection. This heightened expression occurs in response to increased viral protein production, simultaneously leading to elevated dephosphorylation of NP, which accelerates NP polymerization to promote viral replication. Meanwhile, surplus NP can be degraded through the ATG7 autophagy lysosome pathway. Our research elucidates a mechanism that PPM1G maintains vRNP homeostasis by regulating NP status and fate.