BACKGROUND: There is a knowledge gap regarding the effectiveness and utility of various preventive interventions during the COVID-19 pandemic. In this study, we aimed to evaluate the cost-effectiveness of various COVID-19 preventive interventions, including non-medical interventions (NMIs) and vaccination programs, using real-world data across different demographic and socioeconomic contexts worldwide. METHODS: We searched Medline, Cochrane Library, Embase, and Web of Science Core Collection from December 2019 to March 2024. We identified 75 studies which compared 34 COVID-19 preventive interventions. We conducted a network meta-analysis to assess the incremental net benefits (INB) of these interventions from both societal and health care system perspectives. We adjusted purchasing power parity (PPP) and standardised willingness to pay (WTP) to enhance the comparability of cost-effectiveness across different economic levels. We performed sensitivity and subgroup analyses to examine the robustness of the results. RESULTS: Movement restrictions and expanding testing emerged as the most cost-effective strategies from a societal perspective, with WTP-standardised INB values of USD 21 050 and USD 11 144. In contrast, combinations of NMIs with vaccination were less cost-effective, particularly in high-income regions. From a health care system perspective, vaccination plus distancing and test, trace, and isolate strategy were highly cost-effective, while masking requirements were less economically viable. The effectiveness of interventions varied significantly across different economic contexts, underlining the necessity for region-specific strategies. CONCLUSIONS: In this study, we highlight significant variations in the cost-effectiveness of COVID-19 preventive interventions. Tailoring strategies to specific regional economic and infrastructural conditions is crucial. Continuous evaluation and adaptation of these strategies are essential for effective management of ongoing and future public health threats. REGISTRATION: PROSPERO: CRD42023385169.