Ticks are blood-feeding arthropods that may secrete immunosuppressant molecules, which inhibit host inflammatory and immune responses and provide survival advantages to pathogens at tick bleeding sites in hosts. In the current work, two families of immunoregulatory peptides, hyalomin-A and -B, were first identified from salivary glands of hard tick Hyalomma asiaticum asiaticum. Three copies of hyalomin-A are encoded by an identical gene and released from the same protein precursor. Both hyalomin-A and -B can exert significant anti-inflammatory functions, either by directly inhibiting host secretion of inflammatory factors such as tumor necrosis factor-alpha, monocyte chemotectic protein-1, and interferon-gamma or by indirectly increasing the secretion of immunosuppressant cytokine of interleukin-10. Hyalomin-A and -B were both found to potently scavenge free radical in vitro in a rapid manner and inhibited adjuvant-induced inflammation in mouse models in vivo. The JNK/SAPK subgroup of the MAPK signaling pathway was involved in such immunoregulatory functions of hyalomin-A and -B. These results showed that immunoregulatory peptides of tick salivary glands suppress host inflammatory response by modulating cytokine secretion and detoxifying reactive oxygen species.