Background Post-operative pain is frequent following gastrointestinal surgery and may result in prolonged hospitalisation, delayed recovery, and lower quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics and recommended by Enhanced Recovery After Surgery guidelines as part of opioid-sparing multimodal treatment. However, perioperative NSAID treatment may be associated with increased risk of harm. We will investigate the risks of serious adverse events associated with perioperative NSAID treatment in patients undergoing gastrointestinal surgery. Methods This protocol uses the recommendations of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. We wish to assess the effects of NSAIDs versus placebo, usual care, or no intervention on the incidence of serious adverse in patients undergoing gastrointestinal surgery. We will include all randomised trials. To identify trials, we will search the medical literature analysis and retrieval system online, excerpta medica database, cochrane central register of controlled trials, web of science core collection, and BIOSIS. Two authors will screen the literature and extract data. We will use the 'Risk of Bias 2 tool' to assess the risks of systematic errors. We will perform meta-analyses using R. We will use Trial Sequential Analysis to account for the risks of random errors. We will create a "Summary of Findings"-table in which we will present our primary and secondary outcome results. We will assess the certainty of the evidence using grading of recommendations assessment, development and evaluation. Discussion This systematic review can potentially elucidate the risks of perioperative NSAID treatment in gastrointestinal surgery and inform the already established non-opioid multimodal pain treatment regimen recommended by enhanced recovery after surgery guidelines.