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Aim To investigate the relationship between serum 8-hydroxydeoxyguanosine (8-OHdG), chemokine C-X3-C ligand 1 (CX3CL1) and cognitive dysfunction in patients with cerebral small vessel disease (CSVD). Methods 128 patients with CSVD admitted to our hospital from May 2021 to May 2022 were selected and divided into cognitive impairment group and non-cognitive impairment group based on the Montreal cognitive assessment scale (MoCA) scores. The relationship between serum 8-OHdG, CX3CL1 levels and the MoCA scores of CSVD patients was investigated by Pearson correlation analysis, Logistic regression analysis was used to analyze the influencing factors of cognitive impairment in patients with CSVD, and ROC curves were drawn to study the predictive efficacy of serum 8-OHdG and CX3CL1 on cognitive impairment in CSVD patients. Results The serum 8-OHdG and CX3CL1 levels of patients with cognitive impairment were higher than those of non-cognitive impairment group. However, their MoCA scores were lower than those of non-cognitive impairment group (P＜0.05). Serum 8-OHdG and CX3CL1 levels were negatively correlated with MoCA scores (r＝－0.715 and －0.413, P＜0.05). Serum 8-OHdG level was higher in severe cognitive impairment group than that of moderate cognitive impairment group and mild cognitive impairment group (P＜0.05), and it was higher in moderate cognitive impairment group than that of mild cognitive impairment group (P＜0.05). Serum of CX3CL1 level was higher in severe cognitive impairment group than that in moderate cognitive impairment group and mild cognitive impairment group (P＜0.05), and it was higher in moderate cognitive impairment group than that in mild cognitive impairment group (P＜0.05). The area under the ROC curve (AUC) of 8-OHdG for the diagnosis of cognitive impairment in CSVD patients was 0.866, with sensitivity and specificity of 76.53% and 80.00%, respectively (P＜0.05); The AUC of CX3CL1 for the diagnosis of cognitive impairment in CSVD patients was 0.868, with sensitivity and specificity of 86.73% and 80.00%, respectively (P＜0.05); The AUC of the combination of 8-OHdG and CX3CL1 for the diagnosis of cognitive impairment in CSVD patients was 0.922, with sensitivity and specificity of 88.78% and 86.67%, respectively (P＜0.05). Serum 8-OHdG＞2.69 μg/L and CX3CL1＞179.18 pg/L were both influencing factors for cognitive impairment in CSVD patients (P＜0.05).Conclusion The levels of serum 8-OHdG and CX3CL1 are positively correlated with cognitive impairment in CSVD patients, and both can serve as auxiliary indicators for predicting cognitive impairment in CSVD patients.