The aim of this study was to explore the underlying mechanism and function of dexmedetomidine (Dex)-regulated long non-coding RNAs (lncRNAs) in improving postoperative cognitive dysfunction (POCD) in rats. The established POCD model, Dex treatment model in rats, Morris water maze testing, and HE staining assays were used to evaluate the efficacy of Dex in POCD treatment in rats. Hippocampus samples of rats from the POCD group and the Dex group were used for lncRNA sequencing. The expression of five differentially expressed lncRNAs (DElncRNAs) was verified by quantitative reverse transcription PCR (qRT-PCR). Competing endogenous RNAs (ceRNA) network was constructed using Cytoscape. The concentration of inflammatory cytokines were measured by ELISA. Microglia proliferation and apoptosis were assessed using CCK-8 assay and flow cytometry, respectively. In the Dex group, the escape latency was shorter, neuron cell injury levels were alleviated, and the expression levels of TNF-α and IL-1β were significantly down-regulated compared with the POCD group. A total of 60 DE lncRNAs were identified, including 16 up- and 44 down-regulated lncRNAs in the Dex group. KEGG pathway analysis revealed that DElncRNAs were significantly enriched in cytokine–cytokine receptor interactions, the p53 signaling pathway, and the NF-kappa B signaling pathway. The qRT-PCR results and ceRNA network suggested that the lncRNA LOC102546895 may play a key role in POCD. LOC102546895 inhibited proliferation while promoting apoptosis in microglial cells and promoted the mRNA and protein expression of the target gene Npas4. Our findings showed that Dex alleviated POCD in rats and regulated lncRNAs expression profile in the hippocampus tissues of rats with POCD. In conclusion, our study outcome proposes that Dex-regulated lncRNA LOC102546895 may play a role in rats with POCD through targeting Npas4.