Objectives: To compare the effect of cryotherapy, room temperature saline and no saline as final root canal irrigants on post-endodontic pain in patients with symptomatic apical periodontitis.Materials and Methods: An observational study was done at the Endodontics Department of Rehman College of Dentistry, Peshawar from August 2023 to January 2024. Ninety patients were selected via purposive sampling technique and underwent root canal treatment. After root canal preparation, patients were equally divided into three groups using the lottery method: Cryotherapy group, room temperature saline group and no saline group. Pain on percussion was recorded pre-operatively and 24hours post-operatively for every patient using the visual analogue scale. Wilcoxon Signed ranks test was used to assess the signifi cant difference between mean pre-endodontic and post-endodontic pain levels. Post hoc analysis was used to compare the significant difference (p value<0.05) between each group. Results: At 24 hour post-operatively, the mean post-endodontic pain scores on visual analogue scale were 2.50± 1.253 for cryotherapy group, 2.70±2.261 for room temperature saline group and 3.63±1.938 for no saline group. The result shows that the post-endodontic pain reduces signifi cantly in all the three groups(p<0.05). However, cryotherapy as the final irrigant was found to be significantly more eff ective in reducing the post-endodontic pain than no saline as the final irrigant (p value 0.029). No significant difference was found in between the cryotherapy group and the room temperature saline groups (p value 0.964).Conclusion: Cryotherapy as the final root canal irrigant is the most effective method of reducing post-endodontic pain as compared to when no saline was used as the final irrigant. Room temperature saline is also as useful as cryotherapy in reducing post-endodontic pain. The findings of the study will be helpful for the dentists to minimize post-endodontic pain.