Mucus represents an intrinsically antiviral hydrogel that protects mucosal epithelia by trapping and neutralizing pathogens through its dense network of mucin glycans. Building on these natural mechanisms, our research explores mucus reprogramming as a strategy to enhance antiviral defense via molecular design and biophysical engineering. We identify glycopeptides derived from native mucins as versatile building blocks for antiviral biomaterials. These constructs reproduce the spatial arrangement of sialylated glycans, enabling high-avidity interactions with the spike proteins of influenza viruses and thereby efficiently blocking viral attachment and entry (Int. J. Biol. Macromol. 2025, 142357). Complementary to this bottom-up approach, lectin-based mucus engineering reinforces the native mucus layer by anchoring antiviral domains within the mucin network, thereby upgrading the barrier into an active antiviral interface. Together, these approaches demonstrate how molecular reprogramming of mucus composition and interactions can amplify its innate defense properties and inspire the development of programmable, mucus-based biopharmaceuticals for respiratory protection.