We report the identification of novel histamine H4 receptor ligands by ensemble docking on homology model conformers derived from molecular dynamics simulations. Selected receptor models from the trajectories demonstrated superior virtual screening performance compared to the initial models. The ensemble of the best models was able to retrieve a diverse set of known H4 ligands. Prospective virtual screening against these models and subsequent in vitro experimental validation identified novel H4 ligands. Compound 3 showing highest affinity and ligand efficiency represents an interesting scaffold for further medicinal chemistry exploration.