Leukoaraiosis is an important clinical feature of cerebral small vessel disease. To date, there is no reliable biomarker to reflect the degree of cerebral small vessel disease and white matter damage. This study aimed to explore the relationship between cystatin C levels and the degree of white matter damage in order to assess whether cystatin C could serve as a biomarker for white matter damage. We conducted a retrospective analysis of 408 non-critically ill hospitalized patients. The included patients underwent related biochemical and cerebral magnetic resonance imaging examinations. The magnetic resonance imaging results were assessed using the Fazekas scale in fluid attenuation inversion recovery imaging. We analyzed the association of each risk factor (sex, age, blood glucose, blood lipid, and cystatin C) with the degree of white matter damage using univariate logistic and multivariate cumulative odds logistic regression (stepwise). Serum cystatin C concentration was closely associated with the degree of white matter damage (odds ratio =2.14), while age, sex, and hypertension were associated with selective damage of brain white matter. Triglycerides and apolipoprotein A may have a protective effect against white matter damage.