Abstract Histamine was the first canonical monoamine identified in the mammalian brain, yet arguably remains the least understood in its mechanistic contributions to human behaviour. Using a first-in-class causal probe (H 3 R inverse agonist pitolisant), we show how elevating histamine shapes offline and online temporal–hippocampal dynamics — sustaining episodic learning-related activity and polarising retrieval computations. Beyond this, histamine adaptively shifts neurocomputational strategy under high working memory load, while stabilising value updates during aversive reinforcement learning. These findings uncover a mechanistically grounded influence of this underexplored system on human neurocomputation, supporting its therapeutic potential in psychiatry.