Objective: To investigate the effect of bupivacaine (BPV) lipid on cognitive function of elderly anesthesia patients through mitochondrial calcium signal axis modulation. Methods: Sixty-one patients who underwent total hip replacement in our hospital from January 2022 to December 2024 were selected as the research objects and divided into POCD group (n=15) and non-POCD group (n=46). Anesthesia methods were spinal anesthesia combined with bupivacaine liposome for pericapsular nerve block of hip joint. The activity levels of respiratory chain complexes Ⅰ , Ⅱ , Ⅲ , and Ⅳ in mitochondrial membrane of peripheral blood leukocytes were detected by ELISA kit. Forty-eight 18-month-old C57BL/6 male mice were randomly divided into control group, ASM981 group, POCD group and POCD+ASM981 group with 12 mice in each group. Morris water maze was used to evaluate the spatial memory and learning ability of mice. Primary neurons were divided into three groups: blank (Con) group, BPV group, ASM981 group, and BPV+ASM981 group. The expressions of AMP-dependent protein kinase (AMPK) and dynamic related protein 1 (Drp1) were analyzed by western blotting, and MitoTracker Red labeling was used to observe the mitochondria of neurons. Results: The activities of leukocyte mitochondrial membrane respiratory chain complexes Ⅰ , Ⅱ , Ⅲ and Ⅳ in non-POCD group were higher than those in POCD group (P < 0.05). Compared with the POCD group, mice in the POCD+ASM981 group spent less time to escape the incubation period, crossed the platform more times, stayed in the original platform area longer, and greater distance traveled in the target quadrant (P < 0.05). The levels of p-AMPK, mito-Drp1 protein and calcineurin in primary neurons of the BPV+ASM981 group were lower than those of the BPV group (all P < 0.05), while the level of p-Ser637-Drp1 protein was higher than that of the BPV group and the length of mitochondrial branches was longer than that of the BPV group (all P< 0.05). Conclusion: ASM981 has protective effect on cognitive dysfunction induced by BPV in aged mice, and the mechanism may be to improve mitochondrial dysfunction by inhibiting mitosis mediated by AMPK signaling pathway.