A hallmark of chronic inflammatory diseases, including hypertension, is the excessive trafficking of immune cells to the affected tissues, which is coordinated by pro-inflammatory mediators called chemokines. Humans have ~50 chemokines divided into two major classes – CC and CXC chemokines. Specific groups of chemokines are associated with different inflammatory diseases; for example, the chemokines CCL2, CCL7 and CCL8 are upregulated in hypertension. To suppress the host inflammatory response and prolong blood-feeding, ticks have evolved to secrete proteins called “evasins” that bind and block the action of chemokines. Evasins are classified into two major classes – class A and B – with absolute specificity to CC and CXC chemokines, respectively. The class A evasin EVA-P974 from the Cayenne tick (Amblyomma cajennense) binds exclusively to 11 CC chemokines, including two chemokines involved in hypertension (CCL7 and CCL8), but not the other (CCL2). Despite their high potential as clinical anti-inflammatory agents, evasins will need to be modified to selectively target the specific chemokines involved in each disease of interest. To guide the design of targeted evasin variants, we solved three crystal structures of EVA-P974 in complex with the chemokines CCL7 and CCL17 and a CCL8-CCL7 chimera. These structural observations, together with extensive mutagenesis, in vitro binding and functional inhibition data, indicated that the CC chemokine specificity of EVA-P974 is defined through conserved backbone to backbone interactions, whereas its selectivity among CC chemokines is determined by side chain interactions of amino acid residues at N- and C-termini and a hydrophobic pocket in the core region of EVA-P974. Guided by these structure-function data, we engineered EVA-P974 to bind to CCL2 with high affinity binding while retaining tight binding to CCL7 and CCL8. Our findings provide proof-of-principle that class A evasins can be engineered to target specific CC chemokines in inflammatory diseases.