Background The aim of this systematic review (SR) was to assess the safety and efficacy of oral clarithromycin for the treatment of chronic rhinosinusitis (CRS). Methods This SR and meta-analysis was conducted based on the recommendations outlined in the Cochrane Handbook for SR of Interventions. The protocol was registered on PROSPERO, an international prospective register of SRs. English and Chinese electronic databases were searched, and only randomized controlled trials were included. Results Seventeen studies with 1738 patients were included. Eleven studies evaluated whether adding oral clarithromycin to intranasal steroid spray with or without nasal saline irrigation was more effective than intranasal steroid spray alone. This combined treatment regimens statistically significantly improve clinical symptoms in the medium term (1 to 3 months), the endoscopic and computed tomography (CT) scores in both the short term (<1 month) and medium term, and clinical symptoms and the endoscopic score in the long term (>3 months). The incidence of adverse events did not increase with the use of this combination therapy. No significant difference was identified between treatment with oral clarithromycin and intranasal steroid spray alone groups in term of symptoms, endoscopic score, and CT score. Conclusion For the treatment of CRS, adding oral clarithromycin to intranasal steroid spray with or without nasal saline irrigation may achieve better results than using intranasal steroid spray with or without nasal saline irrigation. There is insufficient evidence to confirm that oral clarithromycin alone may have similar efficacy as nasal glucocorticoid spray alone. High-quality evidence in this area is needed.