Epithelial tissues facing the external environment are essential to combating microbial infection. In addition to providing a physical barrier, epithelial tissues mount chemical defenses to prevent invasion of internal tissues by pathogens. Here, we describe that the melanization reaction implicated in host defense is activated in the respiratory system, the trachea, of Drosophila. Tracheal melanization can be activated by the presence of microorganisms but is normally blocked by Spn77Ba, a protease inhibitor in the serpin family. Spn77Ba inhibits a protease cascade involving the MP1 and MP2 proteases that activates phenol oxidase, a key enzyme in melanin biosynthesis. Unexpectedly, we found that tracheal melanization resulting from Spn77Ba disruption induces systemic expression of the antifungal peptide Drosomycin via the Toll pathway. Such signaling between local and systemic immune responses could represent an alarm mechanism that prepares the host in case a pathogen breaches epithelial defenses to invade internal tissues.