The rapid development of new genetic tools has boosted the gene discovery machinery. RNA interference (RNAi), a gene silencing process, has been recently used in several eukaryotic organisms to elucidate the function(s) of unknown genes and biochemical pathways. We used the dsRNA technique in Amlyomma americanum female ticks to test the applicability of the RNAi approach in ticks. Incubation of tick salivary glands (TSGs) in vitro and in vivo injection into whole female ticks with histamine binding protein (HBP) dsRNA led to a reduction in the HBP transcripts in the dsRNA treated groups. The dsRNA-injected ticks had a profound difference in their feeding pattern compared to control ticks that might reflect an increase in local histamine concentrations at the feeding sites. To our knowledge, this is the first RNAi study in ticks. In conclusion, RNAi can be applied in ticks and might be used to test the function of key proteins crucial for avoiding host defense at the tick-host interface.