The histamine H₄ receptor (H₄R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H₄R remains elusive. Here, we report four cryo-EM structures of H₄R/G_i complexes, with either histamine or synthetic agonists clobenpropit, VUF6884 and clozapine bound. Combined with mutagenesis, ligand binding and functional assays, the structural data reveal a distinct ligand binding mode where D94^3.32 and a π-π network determine the orientation of the positively charged group of ligands, while E182^5.46, located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H₄R ligand binding allows us to identify mutants at E182^5.46 for which the agonist clobenpropit acts as an inverse agonist and to correctly predict inverse agonism of a closely related analog with nanomolar potency. Together with the findings regarding receptor activation and G_i engagement, we establish a framework for understanding H₄R signaling and provide a rational basis for designing novel antihistamines targeting H₄R.