Objective To investigate the association between peripheral blood mitochondrial DNA (mtDNA) copy number and disease severity in patients with cerebral infarction.Methods We enrolled 199 cerebral infarction patients diagnosed at Meizhou People's Hospital from January to November 2024. Patients were stratified by NIH Stroke Scale (NIHSS) scores into mild (≤ 4) and moderate-severe (> 4) groups, and further divided into high and low mtDNA groups based on median copy number. Quantitative real-time PCR was used to measure mtDNA levels. Spearman correlation and multivariate logistic regression analyses were performed to assess relationships between mtDNA copy number and clinical parameters.Results Significant differences were observed in age, NIHSS scores, leukocyte and neutrophil counts between severity groups (all P < 0.05). Moderate-severe patients showed significantly lower mtDNA copy numbers than mild cases (P < 0.05). Patients with high mtDNA had lower NIHSS scores than those with low mtDNA (P < 0.05). mtDNA copy number correlated negatively with NIHSS (r? = -0.446, P < 0.001), leukocytes (r? = -0.204, P = 0.004) and neutrophils (r? = -0.221, P = 0.002), and positively with lymphocytes (r? = 0.185, P = 0.009) and triglycerides (r? = 0.167, P = 0.020). Multivariate analysis identified high mtDNA as an independent protective factor against severe infarction (O^R = 0.496, 95% CI: 0.380, 0.647, P<0.05).Conclusion Peripheral blood mtDNA copy number significantly correlates with cerebral infarction severity, suggesting its potential as a circulating biomarker for disease assessment.