The innate immune system initiates immune responses by pattern-recognition receptors (PRR). Virus-derived nucleic acids are sensed by the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family and the toll-like receptor (TLR) family as well as the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). These receptors activate IRF3/7 and NF-κB signaling pathways to induce the expression of type I interferons (IFNs) and other cytokines firing antiviral responses within the cell. However, to achieve a favorable outcome for the host, a balanced production of IFNs and activation of antiviral responses is required. Post-translational modifications (PTMs), such as the covalent linkage of functional groups to amino acid chains, are crucial for this immune homeostasis in antiviral responses. Canonical PTMs including phosphorylation and ubiquitination have been extensively studied and other PTMs such as methylation, acetylation, SUMOylation, ADP-ribosylation and glutamylation are being increasingly implicated in antiviral innate immunity. Here we summarize our recent understanding of the most important PTMs regulating the antiviral innate immune response, and their role in virus-related immune pathogenesis.