<p>Huang Lian Jie Du Decoction (HLJDD) has anti-inflammatory, immunomodulatory, intestinal flora regulation, and anticoagulant effects, but the effects and mechanisms of HLJDD on chronic alcoholic encephalopathy (CAE) remain unclear. This study aimed to investigate the effect and mechanism of HLJDD to improve CAE. CAE mouse model was established, and the mice were treated with different doses of HLJDD according to the principle of randomized controlled trial. Open field test and Morris water maze were used to observe the locomotor and learning memory abilities of mice, hematoxylin–eosin (HE) staining was used to observe the pathological changes in prefrontal cortex and hippocampal CA1, toluidine blue staining was used to detect the neuronal survival in prefrontal cortex and hippocampal CA1, transmission electron microscopy was used to examine neuronal micropathology in prefrontal cortex and hippocampal CA1, and immunofluorescent staining and western blot were used to detect the expression of postsynaptic density protein 95 (PSD95) and synaptophysin (SYN) in hippocampal CA1. Moreover, the changes in gut microbiota were analyzed by 16S rRNA sequencing. The present study found that HLJDD improved the voluntary motor ability and learning memory ability of CAE mice, attenuated prefrontal cortex and hippocampal CA1 damage, and increased the expression of synaptic remodeling-related proteins PSD95 and SYN (<i>P</i> &lt; 0.01), and HLJDD treatment affected the composition of gut microbiota in mice with CAE. HLJDD is an effective traditional Chinese medicine against CAE, and regulating its gut microbiota imbalance.</p>