The relationship between carotid atherosclerosis (AS) and levels of serum cathepsin K (CatK) and cystatin C (CysC) on patients with ischemic cerebral vascular disease (ICVD) was explored. In total, 266 patients with ICVD who were admitted in our hospital were enrolled. According to the results of carotid ultrasound, they were randomly divided into plaque group (n = 133) and control group (n = 133). According to atherosclerotic plaque type distribution, the plaque group was divided into stable plaque group and unstable group. The relationship between levels of serum CatK and CysC of two groups and carotid AS indicator (such as intima-media thickness (IMT)) were analyzed with Spearman’s correlation. Spearman’s correlation analysis showed that IMT level was positively correlated with stability of carotid atherosclerotic plaque (P < 0.05). The level of serum CatK in plaque group was significantly higher than control group, and the level of serum CysC in plaque group was significantly lower than control group (P < 0.05); the level of serum CatK in unstable plaque group was significantly higher than stable plaque group, and the level of serum CysC in unstable plaque group was significantly lower than stable plaque group (P < 0.05). Serum CatK and IMT levels were positively correlated, and serum CysC and CatK levels were negatively correlated (P < 0.05). CatK and CysC levels may be used as serum markers for predicting carotid AS plaque instability, providing a new observational index for prevention and treatment of ICVD caused by carotid AS plaque.