Background: New-onset atrial fibrillation (NOAF) is common in hospitalised patients with critical illness and associated with worse outcomes. Several interventions are available in the management of NOAF, but the overall effectiveness and safety of these interventions compared with placebo or no treatment are unknown. Methods: We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomised clinical trials (RCT) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses, the Cochrane Collaboration, and Grading of Recommendations Assessment, Development and Evaluation statements. We searched RCTs assessing any pharmacological and non-pharmacological treatment compared with placebo or no treatment in critically ill hospitalised patients with NOAF. The primary outcomes were all-cause mortality, adverse events, and health-related quality of life. Results: We included 16 trials (n = 1891) evaluating seven interventions. All trials were adjudicated ‘some concerns’ or ‘high risk’ of bias. The evidence is very uncertain for mortality (RR 0.53, 95% CI 0.03–8.30), adverse events (RR 1.28, 95% CI 0.85–1.92), and treatment efficacy i.e. rhythm control (RR 1.54, 95% CI 1.20–1.97; TSA-adjusted CI 0.56–4.53) between pharmacological treatment and placebo/no treatment (very low certainty evidence). There were no data for health-related quality of life or most of our secondary outcomes. Conclusions: The existing data are insufficient to firmly conclude on effects of any intervention against NOAF on any outcome in hospitalised patients with critical illness. Randomised trials of the most frequently used interventions against NOAF are warranted in these patients.