Aim To investigate the relationship between apical periodontitis and atherosclerosis in rats by lipid profile and carotid artery intima tunic measurement, and histological and histometric evaluation of periapical lesions. Methodology Forty male Wistar rats were allocated into four groups: control (C), with apical periodontitis (AP), with atherosclerosis (AT) and with AP and AT (AP + AT). Atherosclerosis was induced using a high‐lipid diet associated with a surgical ligature in the carotid artery and a super dosage of vitamin D3. AP was induced via pulp exposure to the oral environment. At 45 and 75 days, serum levels of total cholesterol (TC), triglycerides (TG), high‐density lipoprotein cholesterol (HDL‐C) and low‐density lipoprotein cholesterol (LDL‐C) were measured. The maxillary and mandibular jaws and carotid artery were collected and processed for histological analysis. The Kruskal–Wallis or Mann–Whitney test was performed for nonparametric data, and the Tukey’s or Student’s t‐test was performed for parametric data (P < 0.05). Results In nonatherosclerotic animals, the induction of apical periodontitis increased TG levels significantly, from 63.1 ± 11.4 mg dL−1 in group C to 88.2 ± 7.9 mg dL−1 in the AP group (P < 0.05). The induction of AP was associated with a trend for higher TC and LDL‐C levels in atherosclerotic animals (P > 0.05); however, it only significantly increased TG levels, from 93.2 ± 18.0 mg dL−1 in AT group to 121.9 ± 14.5 mg dL−1 in the AP + AT group (P < 0.05). Animals in the AP + AT group had a 36.5% increase in the thickness of the carotid intima tunic when compared with the AT group (P < 0.05). The intensity of the inflammatory infiltrate was significantly larger in the AP + AT group when compared with AP group (P < 0.05). The AP + AT group exhibited significantly greater alveolar bone loss, with a periapical lesion size of 206.4 ± 56.3 × 104 μm2, compared with 151.4 ± 49.1 × 104 μm2 in the AP group (P < 0.05). Conclusion Apical periodontitis influenced triglyceride levels, increasing them even in the absence of atherosclerosis, and influenced the increase in the thickness of the carotid artery intima tunic in the presence of atherosclerosis. Atherosclerosis intensified the inflammatory reaction and increased bone resorption in periapical lesions.