Cardiovascular disease (CVD) is the leading cause of global deaths, with the majority occurring in low- and middle-income countries. The primary and secondary prevention of CVD is suboptimal throughout the world, but the evidence–practice gaps are much more pronounced in low- and middle-income countries. Barriers at the patient, healthcare provider, and health system level prevent the implementation of optimal primary and secondary prevention. Identification of the particular barriers that exist in resource-constrained settings is necessary to inform effective strategies to reduce the identified evidence–practice gaps. Furthermore, targeting modifiable factors that contribute most significantly to the global burden of CVD, including tobacco use, hypertension, and secondary prevention for CVD, will lead to the biggest gains in mortality reduction. We review a select number of novel, resource-efficient strategies to reduce premature mortality from CVD, including (1) effective measures for tobacco control, (2) implementation of simplified screening and management algorithms for those with or at risk of CVD, (3) increasing the availability and affordability of simplified and cost-effective treatment regimens including combination CVD preventive drug therapy, and (4) simplified delivery of healthcare through task-sharing (nonphysician health workers) and optimizing self-management (treatment supporters). Developing and deploying systems of care that address barriers related to the above will lead to substantial reductions in CVD and related mortality.