ObjectiveWe aim to systematically review the literature addressing perioperative practices for optimal use of the CO2 laser in laryngeal transoral laser microsurgery (TOLMS), with a focus on safety.Data SourcesA systematic review of publications indexed in Medline, Embase, and EBM reviews‐Cochrane Central Register of Controlled Trials which evaluated perioperative strategies for the use of CO2 laser in laryngeal TOLMS was conducted.Review MethodsRecords obtained from the search strategy were assessed for eligibility in a 2‐step process by 2 independent researchers using the Covidence software.ResultsAmong 2143 identified records, 103 were included in this study. The majority of studies (n = 25) focused on the use of the CO2 laser in oncologic resection, while 20 addressed the treatment of vocal cord paralysis, 16 discussed the treatment of pediatric or congenital pathologies, 11 detailed the management of benign lesions, and 31 studies tackled other surgical indications. Strategies for safe CO2 TOLMS were highly heterogeneous across studies and included preoperative measures (ie, related to the environment, staff preparation, patient protection, and ventilation), intraoperative precautions (ie, protection of nontarget structures, technical considerations, topical and systemic medications), and postoperative strategies (ie, related to airway protection, oral intake, vocal rest, hospitalization duration, drug regimen, and consultant follow‐up).ConclusionThe results provided in this study can be used as a framework to guide the creation of laser safety protocols across institutions, guide quality improvement initiatives, the development of simulation training activities, and as a tool to facilitate resident teaching and skill assessment.