Objectives As post-endodontic pain control is one of the main targeted addressed in endodontics, our aim was delignated to compare two different methods for low-level laser application utilizing diode laser: low-level laser therapy (LLLT) and laser-activated irrigation (LAI) in the control of post-endodontic pain. Materials and subjects A total of 180 patients received single-visit root canal treatment; they were randomly allocated into 3 equal groups. Group I received LAI, group II received LLLT, and group III served as control with normal root canal treatment and mock laser intervention (ML group). Postoperative pain was recorded using visual analogue scale (VAS) after 24, 48, and 72 h. Data were tabulated and statistically analyzed. Results At 24 h, there was a statistically significant difference between median pain scores in the three groups (P value < 0.001) with ML group scored highest score followed by LAI and then LLLT group. At 48 h, there was a statistically significant difference between the three groups (P value < 0.001), with ML group scoring highest median pain scores while LLLT and LAI showed statistical insignificant scores. At 72 h, there was no statistically significant difference between the 3 groups (P value = 0.179). Conclusion LLLT is superior to LAI and ML group in the control of immediate postoperative pain after 24 h while after 48 h both LAI and LLLT were equally effective, but they still showed significant differences when compared to ML group. Clinical relevance Diode laser can be used by clinicians as it decreases the post-endodontic pain in patients with symptomatic apical periodontitis undergoing endodontic treatment.