INTRODUCTION: Perioperative neurocognitive dysfunction (PND) is a significant challenge for patients who need surgery worldwide. Morphine can trigger an intense inflammatory reaction in the central nervous system (CNS) at the same time as analgesia, thus adverse effects aggravating PND. Microglia polarization is closely involved in the regulation of neuroinflammation and the TLR4/MyD88/NF-κB signaling pathway. However, the mechanisms of morphine analgesia aggravating PND impairment remain unclear. METHODS: Tibial fracture surgery was performed in 18 months old male C57BL/6 J mice to mimic human orthopedic surgery and postoperative analgesia with morphine hypodermic or ropivacaine. Levels of inflammatory factors in the hippocampus, activation, and phenotype of microglia, an essential protein of TLR4/MyD88/NF-κB signal pathway, synaptic plasticity, and hippocampal-dependent memory function were evaluated after surgery and postoperative analgesia. RESULTS: Morphine postoperative analgesia increased the expression of pro-inflammatory cytokines IL-1 β, IL-6, and TNF-α, decreased the level of anti-inflammatory IL-10, aggravated the activation of microglia and the destruction of synaptic plasticity in the hippocampus, resulting in hippocampal neuron loss, a significant decrease in the number of synapses and cognitive impairment in aged mice. In addition, the aggravation of neuroinflammatory response and the activation of microglia may be mediated by TLR4/MyD88/NF- κ B signal pathway. CONCLUSION: Our results demonstrate that morphine postoperative analgesia may aggravate microglia activation and neuroinflammation in the hippocampus by regulating the TLR4/MyD88/NF- κ B signal pathway and inhibiting the synaptic plasticity hippocampal neurons. It aggravated the acute cognitive decline and cognitive impairment after tibial fracture in elderly mice.