AimThe pathways to post‐operative pain are complex and encompass factors that extend beyond the treatment protocol employed. This study aimed to identify patient‐related predictors of post‐operative pain following root canal treatment.MethodologyA total of 154 patients received a single‐visit root canal treatment for asymptomatic necrotic mandibular molars. Before treatment, dental anxiety, dental fear and sense of coherence (SOC) were measured as predictors for each patient using validated questionnaires. Other measured predictors included gender, age, previous negative experiences at the dental offices and prior root canal treatment. Post‐operative pain was assessed using the Numeric Rating Scale at multiple time‐points over 30 days. Structural equation analysis was employed to evaluate the direct and indirect effects of patient‐related predictors on a theoretical model of post‐operative pain. The irrigant solution was also included in the model, as it was the only aspect that varied in the treatment protocol (sodium hypochlorite 2.5% and 8.25%).ResultsDental anxiety (coefficient 0.028; p < .01), dental fear (coefficient 0.007; p = .02) and irrigant solution (coefficient 0.004; p = .03) exerted a direct effect on post‐operative pain. SOC exerted an indirect effect on post‐operative (coefficient 0.006; p = .01) through dental anxiety and dental fear. Moreover, previous negative experiences (coefficient 0.048; p = .04) exerted an indirect effect on post‐operative pain through dental anxiety.ConclusionsDental anxiety, dental fear, previous negative experiences and SOC are patient‐related predictors of post‐operative pain following root canal treatment. These factors should be taken into consideration in clinical practice, as patients with these characteristics may be at an increased risk of experiencing post‐operative pain.