AimThis study aimed to investigate the potential protective effects of N‐acetyl‐L‐cysteine (NAC) against apical periodontitis (AP) in rats with adriamycin (ADR)‐induced kidney and heart diseases.MethodologyFourty‐eight Wistar albino rats were divided into six groups: (1) Control group, (2) ADR group (1 mg/kg/day ip for 10 days), (3) AP Group (1st mandibular molar tooth), (4) AP + ADR Group, (5) AP + NAC group (150 mg/kg/day ip), and (6) AP + ADR + NAC group. After 3 weeks, the rats were decapitated and blood and tissue samples (heart, kidney, and jaw) were collected. Tissue samples were evaluated by biochemical (inflammatory cytokines and hemodynamic parameters) and radiological analyses. One‐way anova with Tukey post hoc tests was used to compare data, considering p < .05 as statistically significant.ResultsThe serum levels of TNF‐α, IL‐1β, BUN, Creatinine, CK, and LDH were elevated in the test groups compared with the control group, and treatment with NAC reduced these levels (p < .05). Heart and kidney tissue analysis showed a higher heart‐to‐body weight ratio (HW/BW) and kidney‐to‐body weight ratio (KW/BW) in the test groups compared with the control group (p < .05). No significant differences in HW/BW and KW/BW were found between the control and AP + NAC groups. Volumetric apical bone resorption analysis showed an increase in periapical radiolucencies in AP‐induced groups indicating apical periodontitis. NAC treatment reduced the total area and volume of resorption cavities (p < .05).ConclusionsThe results suggest that NAC's antioxidant and anti‐inflammatory effects can reduce adriamycin‐mediated heart and kidney damage and may have a positive effect on apical periodontitis in individuals with nephropathy and cardiomyopathy.