Background: New-onset atrial fibrillation is frequent in critically ill patients and associated with poorer outcomes in these patients. Numerous interventions are used for the management of new-onset atrial fibrillation, but it is unknown if these interventions improve patient-important outcomes as compared with placebo or no active intervention in adult critically ill patients. Methods/design: We will conduct a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials assessing pharmacological and non-pharmacological interventions of new-onset atrial fibrillation as compared with placebo or no active intervention in adult critically ill patients. The primary outcomes are mortality, adverse events and health-related quality of life. We will search the following databases: MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov, Science Citation Index and BIOSIS and follow the recommendations by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We will evaluate the overall certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Discussion: New-onset atrial fibrillation is common in adult critically ill patients. However, the balance between the desirable and undesirable effects of pharmacological and non-pharmacological interventions is unknown. The outlined systematic review aims to provide updated data on this topic. Registration: Submitted to PROSPERO (CRD42020187178). Status: accepted.