Objective To explore the correlations of serum levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and their ratios, with the severity of white matter hyperintensities (WMH) in patients with cerebral small vessel disease (CSVD). Methods This prospective study included patients with CSVD who were treated at Zhongshan Hospital, Xiamen University between January 2022 and February 2024. Qualitative and quantitative analyses of WMH were performed using the Fazekas scale and lesion prediction algorithm. Biomarkers such as MMP-2, MMP-9, and TIMP-1 were measured to explore their correlations with the severity of WMH. Results A total of 144 patients with CSVD were included in this study, comprising 63 males and 81 females, with an average age of (67.60±8.73) years. There were 83 (57.6%), 41 (28.5%), and 20 (13.9%) patients were categorized as Fazekas grade 1, 2, and 3 for WMH, respectively, with an median total WMH volume of 4.31 mL. Multinomial logistic regression analysis for Fazekas grade (grade 1 as the reference level) showed that MMP-2 [grade 2: odds ratio (OR)=1.059, 95% confidence interval (CI) (1.016, 1.105); grade 3: OR=1.463, 95%CI (1.124, 1.905)], TIMP-1 [grade 2: OR=1.019, 95%CI (1.006, 1.032); grade 3: OR=1.048, 95%CI (1.008, 1.090)], and MMP-9/TIMP-1 [grade 3: OR=2.650, 95%CI (1.393, 5.039)] were independently associated with Fazekas grade (P<0.05). Multinomial logistic regression analysis for the quartile group of total WMH volume (group Q1 as the reference level) showed that MMP-2 [group Q2: OR=1.160, 95%CI (1.021, 1.318); group Q3: OR=1.238, 95%CI (1.086, 1.412); group Q4: OR=1.313, 95%CI (1.140, 1.512)] and TIMP-1 [group Q2: OR=1.095, 95%CI (1.054, 1.138); group Q3: OR=1.084, 95%CI (1.045, 1.125); group Q4: OR=1.102, 95%CI (1.057, 1.149)] were independently associated with the quartile group of total WMH volume (P<0.05). Conclusions Serum levels of MMP-2 and TIMP-1 demonstrate significant independent associations with both the Fazekas grade and the total volume of WMH in patients with CSVD. These correlations underscore the potential utility of MMP-2 and TIMP-1 as critical biomarkers for assessing the severity of WMH in CSVD, highlighting their prospective roles in clinical diagnostics and therapeutic monitoring.