Objectives: The current systematic review and meta‐analysis aimed to assess the efficacy of prophylactic oral antibiotics in the management of post‐operative endodontic symptoms in adults with necrotic pulp. Materials and methods: A systematic search up to April 2020 was performed to find all randomised controlled trials (RTCs) comparing oral antibiotics with placebo to manage post‐endodontic symptoms. The outcome measures were post‐operative pain, swelling and/or the combined pain and swelling at different follow‐ups. Standardised mean differences (SMDs) and 95% confidence intervals (CIs) were estimated using random‐effect inverse‐variance method. Additional analysis was performed if heterogeneity existed (P <.05). Results: For post‐endodontic pain, 8 RCTs (n = 690) were included. Antibiotic prescription had no significant effect on endodontic pain at 6 (SMD = −0.008, 95% CI −0.279 − 0.264, P =.95), 12 (SMD = −0.080, 95% CI −1.39 − 1.23, P =.90), 24 (SMD = −0.044, 95% CI −0.29 − 0.20, P =.72), 48 (SMD = 0.18, 95% CI −0.26 − 0.62, P =.42) and 72 h (SMD= −0.050, 95% CI −0.33 − 0.23, P =.723) post‐operatively. For post‐endodontic swelling, 4 RCTs (n = 149) were included. Antibiotic prescription had no significant effect on endodontic swelling at 24 (SMD = 0.29, 95% CI −0.72 − 1.32, P =.56), 48 (SMD = −0.23, 95% CI −0.98 − 0.51, P =.54) and 72 hours (SMD= −0.03, 95% CI −1.25 − 1.33, P =.96), post‐operatively. For combined pain and swelling, no meta‐analysis was performed. Conclusion: The administration of prophylactic antibiotics to prevent post‐operative endodontic symptoms is not supported by the current evidence. [ABSTRACT FROM AUTHOR]