Aims: To analyze and compare the adverse events (AEs) and adverse drug reaction (ADRs) associated with pirfenidone and nintedanib, two antifibrotic drugs commonly used in the treatment of idiopathic pulmonary fibrosis (IPF), based on real-world data. Methods: We collected reports from the FD Adverse Event Reporting System (FAERS) and VigiAccess databases. Two main disproportional analysis, including reporting odds ratio (ROR) and proportional reporting ratio (PRR), were conducted to determine the association of these drugs with signals at both the preferred term (PT) and system organ class (SOC) levels. Results: A total of 55,949 reports for pirfenidone and 35,884 reports for nintedanib were obtained from the FAERS database. Correspondingly, the VigiAccess database provided 37,187 reports for pirfenidone and 23,134 reports for nintedanib. Male patients and individuals over the age of 65 were more likely to report AEs for both drugs. Gastrointestinal disorders emerged as the most significant signal at SOC level for both pirfenidone and nintedanib. Additionally, signals such as nausea, diarrhoea and decreased appetite were notable at PT level. Furthermore, we also identified signals, including hemiplegic migraine for pirfenidone and asthenia, constipation, as well as flatulence for nintedanib, which were previously unknown or underestimated risks. Conclusion: This study identified AEs and ADRs of pirfenidone and nintedanib in the treatment of IPF, confirming the most of the corresponding label information is relatively safe. However, some unexpected risk signals should be taken seriously, and further research is needed to manage the safety profiles of these drugs in IPF patients.