Chemokines and their receptors are central regulators of immune cell trafficking during both immune surveillance and pathological inflammation. In autoimmune and inflammatory diseases, as well as in cancer, dysregulated chemokine networks drive persistent immune cell infiltration. Despite decades of research, therapeutic strategies targeting individual chemokines or their receptors have largely failed, reflecting the redundancy and complexity of the chemokine system, in which multiple chemokines act in concert. Our research addresses this challenge by developing agents that can simultaneously neutralize groups of functionally related chemokines. We exploit the unique properties of tick salivary proteins, known as “evasins,” which naturally bind multiple chemokines. Through structural and mutagenesis studies, we have gained detailed insights into how chemokines interact with evasins. We integrate these insights with AI-driven protein design to generate de novo multi-chemokine inhibitors. In addition, using an in vitro evolution system coupled with next-generation sequencing, we have engineered variants with tailored chemokine selectivity. This work provides a framework for designing multi-chemokine inhibitors that selectively target subsets of chemokines implicated in disease and establishes a versatile discovery platform for next-generation biologics.