Objective To construct a whole-of-system model to inform strategies that reduce the burden of cardiovascular disease (CVD) in Australia. Methods A system dynamics model was developed with a multidisciplinary modelling consortium. The model population comprised Australians aged 40 years and over, and the scope encompassed acute and chronic CVD as well as primary and secondary prevention. Health outcomes were CVD-related deaths and hospitalisations, and economic outcomes were the net benefit from both the healthcare system and societal perspectives. The eight strategies broadly included creating social and physical environments supportive of a healthy lifestyle, increasing the use of preventive treatments, and improving systems response to acute CVD events. The effects of strategies were estimated as relative differences to the business-as-usual between 2019–2039. Probabilistic sensitivity analysis produced uncertainty intervals of interquartile ranges (IQR). Findings The greatest reduction in CVD-related deaths was seen in strategies that improve systems response to acute CVD events (8.9%, IQR: 7.7–10.2%), yet they resulted in an increase in CVD-related hospitalisations due to future recurrent admissions (1.6%, IQR: 0.1–2.3%). This flow-on effect highlighted the importance of addressing underlying CVD risks. On the other hand, strategies targeting the broad environment that supports a healthy lifestyle were effective in reducing both hospitalisations (7.1%; IQR: 5.0–9.5%) and deaths (8.1% reduction; IQR: 7.1–8.9%). They also produced an economic net benefit of AU$43.3 billion (IQR: 37.7–48.7) using a societal perspective, largely driven by productivity gains. Overall, strategic planning to reduce the burden of CVD should consider the varying effects of strategies over time and beyond the health sector.