Background: Pain of endodontic origin can be annoying for patients and endodontist. Pain relief is more important to the patient than treatment success. Numerous factors such as over instrumentation, over filling, debris extrusion can cause postoperative pain. However, bacteria found in the root canal space is the most important factor. Therefore mechanical preparation is an important step in elimination of micro-organisms from the root canal. It has been reported that micro-organisms can still survive inside the root canal even after mechanical preparation. Hence, the use of intra-canal medicaments in between visits for reduction of bacteria inside the root canal space has been recommended. The aim of this study was to assess the ability of silver nanoparticles versus calcium hydroxide used as intra-canal medication in reducing pain in necrotic teeth with apical periodontitis. Methods: Thirty-four participants were randomly divided into 2 groups, 17 in each group according to intra-canal medication used silver nanoparticles and calcium hydroxide (AgNPs and Ca(OH)2). Each patient was given pain scale chart numerical rating scale (NRS) in order to record his/her pain level before any intervention followed by placement of intra-canal medicament for 1 week. Postoperative pain was recorded at 4, 12, 24, 48 hours. Results: Pre-operatively; there was no statistically significant difference between mean pain scores in the two groups. After 4, 12 as well as 24 hours, Ca(OH)2 group showed statistically significantly higher mean pain score than AgNPs group. After 48 hours; there was no statistically significant difference between mean pain scores in the two groups. Conclusions: There was a statistically significant difference in postoperative pain following 4, 12, and 24 hours where AgNPs group resulted in reduction of pain more than Ca(OH)2 group. At 48 hours, there was no statistically significant difference. Trial registration: PACTR PACTR201602001444180 26/01/2016