Objective <p>To investigate the effect of Tiaobu Xinshen Recipe (TXR) on cognitive function of 5xFAD transgenic mice and explore the potential mechanisms.</p> Methods <p>Six-month-old male wild-type (WT) mice and 5xFAD transgenic mice were randomly divided into vehicle (0.9% NaCl), TXR (granules, 4.18 g/kg) and donepezil (0.625 mg/kg) groups using a random number table, respectively, which were given intragastric administration once a day for 60 d. Spatial learning and memory performance was tested with modified Morris water maze (MMWM) test. Synaptic ultrastructure in the hippocampal CA1 region was observed by transmission electron microscopy. The levels of amyloid β (Aβ), the major amyloid precursor protein (APP)-cleaving enzymes and Aβ-degrading enzymes including β-secretase, α-secretase, neprilysin (NEP) and insulin-degrading enzyme (IDE), were detected by immunohistochemistry staining and Western blot, respectively.</p> Results <p>In MMWM test, when compared with the 5xFAD-vehicle group, 5xFAD-TXR group demonstrated a significantly shorter escape latency to the platform and increased number of platform crossings and time spent in target quadrant (<i>P</i>&lt;0.05 or <i>P</i>&lt;0.01). The ultrastructure of synapse in the hippocampal CA1 region of mice in the 5xFAD-TXR group was significantly changed, including increased numbers of mitochondria and synaptic vesicles, intact synaptic membrane, and thickened postsynaptic density. The Aβ load was markedly decreased in the cerebral cortex and hippocampus CA1 subregion of TXR-treated 5xFAD mice (<i>P</i>&lt;0.05). TXR treatment decreased APP levels and increased IDE expression in brains of 5xFAD mice (<i>P</i>&lt;0.01). However, TXR treatment had no effect on α- and β-secretase, and NEP in 5xFAD mice (<i>P</i>&gt;0.05).</p> Conclusion <p>TXR improves cognitive dysfunction in 5xFAD mice by alleviating synaptic ultrastructure degradation and reducing Aβ.</p>