IntroductionObstructive sleep apnoea (OSA) is a common disorder that can affect the quality of life and increase the risk for psychiatric, neurological and cardiometabolic diseases. Despite the significant burden, it poses on health and well-being, there is a lack of evidence regarding the use of drug therapies in these patients. This work aims to evaluate the efficacy and safety of pharmacological treatment alternatives for patients with OSA.Methods and analysisDatabases, including PubMed, Embase, Web of Science, SciELO, LILACS, Scopus, Cochrane Register of Controlled Trials and ClinicalTrials.gov, will be used for the search. A search strategy was developed to retrieve clinical trials that have evaluated polysomnographic primary outcome (Apnoea-Hypopnoea index) and secondary outcomes (eg, daytime sleepiness, adverse events) of any drug therapy used for OSA. No date or language restrictions will be applied. Two authors will independently select the studies meeting the inclusion criteria by screening the title, abstract and full text. Data will be extracted, and the risk of bias will be evaluated using the Cochrane Risk of Bias Tool. Review Manager V.5.4.1 will be used for data synthesis. The Grading of Recommendation Assessment, Development and Evaluation will be used to assess the strength of the evidence.Ethics and disseminationAs a review of published data, it is not necessary to obtain ethical approval. The findings of this systematic review will be published in a peer-reviewed journal.PROSPERO registration numberCRD42022362639.