Background: Postoperative pain is defined as pain of any degree after initiation of endodontic treatment either intra-appointment or post-obturation and is considered an undesirable occurrence for both patient and dentist. It was suggested that bacterial injury is probably the major cause of pain. Intra-canal medicaments are widely used to kill any bacteria surviving after instrumentation and irrigation. The aim of this study was to assess the ability of double antibiotic paste versus calcium hydroxide used as intra-canal medication in reducing postoperative pain. Methods: 36 patients with single rooted necrotic premolars with apical periodontitis were randomly assigned into two groups according to the intra-canal medication used: calcium hydroxide group (CH) and double antibiotic paste group (DAP). Preoperative pain was recorded using numerical rating scale. After isolation, access cavity was performed followed by chemico-mechanical preparation using rotary Race files with 2.5% sodium hypochlorite irrigation. Subsequently, intra-canal medication was placed and postoperative pain was recorded at 6, 12, 24 and 48 hours postoperatively. Results: There was no statistically significant difference between both groups. Both groups resulted in an increase in median pain value from preoperative to 6 hours postoperative, followed by gradual decrease from 6 hours to 12, 24, 48 hours postoperatively with statistically significant difference. When comparing both groups, DAP group showed lower postoperative pain values than CH group at 12 and 24 hours, but this was not statistically significant. Conclusion: The use of intra-canal medication in necrotic teeth with apical periodontitis was efficient in reducing postoperative pain regardless of type of intra-canal medication used. Trial registration: PACTR201605001482394 (Date: 22 nd February 2016).