Objective To investigate the effect of the change in blood pressure variability on white matter lesions (WMLs) under different antihypertensive strategies in hypertensive patients. Methods A total of 274 hypertensive patients who were consecutively admitted to the Department of Neurology in Zhengzhou People's Hospital from January 2013 to March 2018 were enrolled. Ambulatory blood pressure (ABP) measurement and head MRI were performed on day 2 after admission. According to the presence or absence of WMLs, these patients were divided into non-WML group with 72 patients, mild-to-moderate WML group with 120 patients, and severe WML group with 82 patients. Clinical data were compared between groups, and a multivariate analysis was performed to identify the risk factors for WMLs. Blood pressure variability and the severity of WMLs were compared between patients treated with different antihypertensive drugs. Results There were significant differences between the three groups in 24-hour coefficient of systolic pressure variation and 24-hour standard deviation of systolic pressure (χ²=32.492 and 25.518, P=0.000 and 0.000). The 24-hour coefficient of systolic pressure variation (odds ratio[OR]=2.987, 95% confidence interval[CI]:1.537-5.806, P=0.001) and 24-hour standard deviation of systolic pressure (OR=2.046, 95% CI:1.042-4.018,P=0.038) were independent risk factors for WMLs. Compared with those treated with β-receptor blocker, the patients treated with calcium antagonists had significantly lower blood pressure variability (χ²=16.615,P=0.000) and severity of WMLs (χ²=18.972,P=0.000). Conclusions The 24-hour standard deviation and coefficient of systolic pressure variation are good and simple indices for predicting WMLs. Avoiding drastic fluctuation of blood pressure and using appropriate antihypertensive drugs are effective measures for the prevention of WMLs.