Nearly half of Americans are employed by small businesses, and future projections suggest that the number of those employed by small businesses will rise. Despite this, there is relatively little small business intervention research on the integration of health protection and health promotion, known as Total Worker Health® (TWH). We first discuss the importance of studying small businesses in TWH research and practice. Second, we describe an example of a small business TWH intervention, Health Links™ plus TWH owner/senior manager leadership training, that we are evaluating via the Small+Safe+Well (SSWell) study. Key features of the intervention and the SSWell study include attention to multi-level influences on worker health, safety and well-being; organizational change; and dissemination and implementation science strategies via the RE-AIM model. We offer several considerations for future small business TWH research and practice both in terms of the small business context as well as intervention development and evaluation. Our goal is to provide TWH researchers and practitioners with a framework and an example of how to approach small business TWH interventions. Ultimately, through the SSWell study, we aim to provide small businesses with strong evidence to support the use of TWH strategies that are practical, effective and sustainable.