Abstract There has been an increasing recognition on the importance and the value of addressing social determinants of health (SDoH) to improve population health outcomes, manage healthcare costs and reduce health inequities. Despite the strong interest in investing in SDoH initiatives by various stakeholders, the literature on the return from such investments is scarce. The differences in study populations and methodologies, and the lack of data on SDoH intervention outcomes and/or costs makes it challenging to quantify and generalize outcomes for decision making. We reviewed the literature on SDOH interventions focused on food and housing insecurity, and developed a methodology for estimating a key outcome: the return on investment (ROI), defined as the net returns from an intervention divided by its costs. The ROI estimates we report can be used by stakeholders to prioritize among alternative SDoH interventions for fundraising, investing and implementing purposes. The average ROI for food insecurity programs was 85% (ranging from 1% to 287%, except for one -31%), and housing insecurity programs 50% (ranging from 5% to 224%, except for one -38%). In addition, these estimates can serve as key inputs for designing and employing innovative financing and policy solutions to increase the use of these interventions.