Serine proteases are a class of enzymes that orchestrate an immune response. These proteases can be hijacked by viruses to facilitate entry and spread, while simultaneously supporting the innate immune system in neutralizing pathogens. This review highlights the dual roles of exogenous serine proteases, emphasizing neutrophil serine proteases (NSPs) that facilitate viral entry and promote disease progression while also contributing to antiviral defense by degrading viral glycoproteins. Additionally, the potential to modulate serine protease activity to boost host defenses will be discussed, offering both significant challenges and new opportunities for therapeutic intervention.