Increasing evidence suggests an association between non-steroidal anti-inflammatory drugs (NSAIDs) and atrial fibrillation in the general population. A systematic review was conducted to characterize the association of perioperative NSAIDs with atrial fibrillation after non-cardiac surgery (POAF). PubMed and Scopus were searched for relevant studies. We excluded review articles, case studies, articles not published in English, and animal studies. The primary objective was to investigate the relationship between the perioperative use of NSAIDs and POAF during the first 30 postoperative days (from the day of surgery), at hospital discharge, and at 30 and 90 days after hospital discharge. Four studies were identified, a pooled analysis of two randomized double-blind clinical trials and three observational studies. A post-hoc sensitivity analysis for acetylsalicylic acid (aspirin) vs. other NSAIDs revealed that the former seems to decrease the incidence of POAF although non-significantly (Relative Risk (RR) (95% Confidence Interval (CI)): 0.92 (0.81, 1.04); p = 0.165). After excluding acetylsalicylic acid from the analysis, NSAIDs were associated with an increased risk of POAF development (RR (95% CI): 1.15 (1.07, 1.23); p < 0.001). In conclusion, perioperative administration of non-aspirin NSAIDs may be associated with an increased risk of POAF development. Further studies investigating the role of NSAIDs and the potential protective role of aspirin in POAF are justified.