Objective The aim of this study is to investigate the effects of serum high-sensitivity C-reactive protein (hsCRP) and the pathological changes in the carotid artery after periodontal mechanical therapy with local and systemic drugs in SD rats with chronic periodontitis (CP) associated with atherosclerosis (As).Methods Thirty-five SD rats were randomly divided into two groups: control group (group A) and CP+As group (group B). Group B was further divided into the natural process group (B1), the periodontal mechanical treatment group (B2), the periodontal mechanical treatment plus local drugs group (B3), and the periodontal mechanical treatment plus local and systemic drugs group (B4). Each group comprised seven rats. Serum hsCRP levels were evaluated at baseline 1 week after the first periodontal therapy and 1, 3, and 5 weeks after the second periodontal therapy by enzyme linked immunosorbent assay (ELISA). The pathological lesion in the carotid artery plaque was stained with hematine and eosin.Results The levels of serum hsCRP in group B1 increased gradually as time passed and became significantly higher than that of the other groups five weeks after periodontal therapy (PConclusion Direct periodontal mechanical treatment results in acute, short-term, systemic inflammation and might increase the risk of atherosclerosis in SD rats. However, the levels of serum hsCRP decreased gradually 3 to 5 weeks after therapy. With periodontal mechanical treatment, the benefits of local and systemic drugs are associated with improvement in atherosclerotic lesion progression.