A method that promotes the retrieval of lost long-term memories has not been well established. Histamine in the central nervous system is implicated in learning and memory as well as sleep and wakefulness, feeding and drinking, and neuroendocrine regulation, and treatment with antihistamines impairs learning and memory. Since histamine H3 receptor inverse agonists upregulate histamine release, histamine H3 receptor inverse agonists may enhance learning and memory. However, whether H3 receptor inverse agonists promote the retrieval of forgotten long-term memory has not yet been determined. Here, we employed multidisciplinary methods including the mouse behavior, calcium imaging and chemogenetic manipulation to examine whether and how the histamine H3 receptor inverse agonists, thioperamide and betahistine, promote the retrieval of a forgotten long-term object memory in mice. The treatment of H3 receptor inverse agonists induced the recall of forgotten memories even 1 week and 1 month after training in mice. In addition, we found a betahistine treatment promote memory retrieval in humans. These results highlight a novel interaction between the central histamine signaling and memory engrams.