Aim To investigate the effects of liver fibrosis (LF) on the pro‐inflammatory mediators and periapical bone resorption of apical periodontitis (AP) in rats. Methodology Forty male Wistar rats were distributed into four groups: C – control, AP – rats with AP, LF – rats with LF, AP + LF – rats with AP and LF. LF was induced by carbon tetrachloride administration for 8 weeks and surgical bile duct ligation for 4 weeks; AP was induced in the teeth of rats by dental pulp exposure to the oral environment for 30 days. Jaws and livers were removed after euthanasia. Haematoxylin and Eosin (H&E) and Picrosirius Red (PSR) staining were used to confirm fibrosis in the livers. The jaws were analysed using H&E staining, immunohistochemical assays of interleukin (IL)‐1β, IL‐6 and tumour necrosis factor‐alpha (TNF‐α). Student’s t‐test and Mann–Whitney’s U‐test were used for statistical analysis (P < 0.05). Results Inflammatory infiltrate was moderate in the AP group and severe in the AP + LF group (P < 0.05). Periapical bone resorption was significantly larger in the AP + LF group compared with the AP group (P < 0.05). IL‐1β, IL‐6 and TNF‐α levels were significantly higher in AP + LF group when compared to the AP group (P < 0.05). Conclusion More intense inflammatory infiltrate, greater amounts of pro‐inflammatory cytokines and increased periapical bone resorption were observed in the presence of liver fibrosis in rats with exposed pulps.