Systematic review tools and approaches developed for clinical medicine are often difficult to apply “off the shelf” in order to meet the needs of chemical risk assessments. To address such, we propose an approach that can be used by practitioners for using evidence-based methods to facilitate the risk assessment process. The framework builds on and combines efforts conducted to date by a number of agencies and researchers; the novelty is in combining these efforts with a practical understanding of risk assessment, and translating such into a ‘step-by-step’ guide. The approach relies on three key components: problem formulation, systematic evidence mapping, and systematic review, applied using a stepwise approach. Unique to this framework is the consideration of exposure in selecting, prioritizing, and evaluating data (e.g., dose-relevance, routes of exposure, etc.). Using the proposed step-by-step process, critical appraisal of individual studies (e.g., formal and structured assessment of both relevance and reliability) and integration efforts are considered in context of specified risk assessment objectives (e.g., mode of action, dose-response) as well as chemical-specific considerations. The resulting framework provides a logical approach of how evidence-based methods can be used to facilitate risk assessment, and elevates the use of systematic methods beyond hazard identification to directly facilitating transparent and objective selection of candidate studies and/or datasets used to quantitatively characterize risk, and to better use the underlying process to inform the approaches used to develop toxicity values.