Background: The evidence of different analgetics for acute renal colic was uncertain. We aimed to comprehensively assess the efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, paracetamol, combination therapy, and placebo for treatment of acute renal colic. Methods: We did a systematic review and network meta-analysis. We searched Ovid MEDLINE, Ovid EMbase, the Cochrane Library, Clinical Trials Registry Platform for Clinicaltrials.gov, and WHO International Clinical Trials Registry Platform through February 2, 2018. All randomised controlled trails (RCTs) regarding NSAIDs, opioids, paracetamol, combination therapy, and placebo were identified for analysis. In network meta-analysis, we used group-level data. The primary outcome was pain variance at 30 min. To obtain the most reliable results, we designed a three-stage strategy based on classification and pharmacological mechanisms in the first stage, routes of administration in the second stage, and specific drug branches with different routes in the third stage. We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with fixed and random effects. Findings: We identified 65 studies with 8633 participants for analysis. In the first stage, we found that combination therapy was more efficient than NSAIDs for the primary outcomes at the cost of safety. Opioids gave rise to more nonspecific adverse events and vomiting events compared with other interventions. NSAIDs were superior to opioids, paracetamol, combination therapy and placebo after a full consideration of all outcomes. In the second stage, NSAIDs sused with an intravenous (IV) route or intramuscular (IM) route ranked first in all interventions with different routes from an efficacy or safety perspective, respectively. In the third stage, ibuprofen used with an IV route, ketorolac with an IV route and diclofenac with an IM route were superior for the management of acute renal colic. The results from diclofenac using the IM route were more reliable than those from ibuprofen used with an IV route and ketorolac with an IV route. Interpretation: This network meta-analysis suggests that NSAIDs are superior to opioids, paracetamol, combination therapy and placebo and NSAIDs with the IV route or IM route ranked the highest. Furthermore, our study recommends that diclofenac used with an IM route as more reliable results for the management of acute renal colic for patients who do not have risks of cardiovascular events. For other patients with risks of cardiovascular events, different NSAIDs could be used or diclofenac IM could be used after careful consideration. Because there were only a few studies, the results of ibuprofen using the IV route and ketorolac using the IV route need to be verified. Trial Registration No.: This study is registered with PROSPERO, number CRD42018087906. Funding: None. Conflict of Interest: We declare no competing interests.