This study aimed to investigate the impact of alcohol (A), secondhand cigarette smoking (ShS), and their combined effect on liver antioxidant activity and hepatic damage in rats with induced apical periodontitis (AP). Thirty-five female Wistar rats were randomly allocated into five groups (n = 7): (1) control (rats without ShS, alcoholic diet, or AP), (2) control-AP (induced AP only), (3) ShS-AP (ShS exposure and induced AP), (4) A-AP (alcoholic diet and induced AP), and (5) A+ShS-AP (alcoholic diet, ShS exposure, and induced AP). Alcohol was administered through semi-voluntary intake, while ShS exposure involved the daily inhalation of cigarette smoke. The experimental period lasted 8 weeks, with AP induction occurring in the 4th week following molar pulp exposure. Liver samples were collected post-euthanasia for histomorphometric and antioxidant marker analyses. All AP-induced groups exhibited increased liver sinusoidal dilation compared to the control group (p < 0.05). AP significantly reduced total antioxidant capacity (FRAP) across all groups (p < 0.05). In AP-induced groups, FRAP levels were further decreased in ShS-AP and A+ShS-AP compared to control-AP (p < 0.05). AP also led to a decrease in the glutathione defense system (p < 0.05). Rats with alcohol exposure (A-AP and A+ShS-AP) showed reduced glutathione peroxidase activity (p < 0.05). Glutathione reductase activity was comparable in the control and control-AP groups (p > 0.05), but significantly decreased in the alcohol and ShS-exposed groups (p < 0.05). Apical periodontitis can relate to morphological changes in the liver’s sinusoidal spaces and impairment of liver’s antioxidant capacity of rats, particularly when combined with chronic alcohol consumption and exposure to cigarette smoke.