Background: The prevalence of inadequate symptom control among cancer patients is quite high despite the availability of definitive care guidelines and accurate and efficient assessment tools. Methods: We will conduct a hybrid type 2 stepped wedge pragmatic cluster randomized clinical trial to evaluate a guideline-informed enhanced, electronic health record (EHR)-facilitated cancer symptom control (E2C2) care model. Teams of clinicians at five hospitals that care for patients with various cancers will be randomly assigned in steps to the E2C2 intervention. The E2C2 intervention will have two levels of care: level 1 will offer low-touch, automated self-management support for patients reporting moderate sleep disturbance, pain, anxiety, depression, and energy deficit symptoms or limitations in physical function (or both). Level 2 will offer nurse-managed collaborative care for patients reporting more intense (severe) symptoms or functional limitations (or both). By surveying and interviewing clinical staff, we will also evaluate whether the use of a multifaceted, evidence-based implementation strategy to support adoption and use of the E2C2 technologies improves patient and clinical outcomes. Finally, we will conduct a mixed methods evaluation to identify disparities in the adoption and implementation of the E2C2 intervention among elderly and rural-dwelling patients with cancer. Discussion: The E2C2 intervention offers a pragmatic, scalable approach to delivering guideline-based symptom and function management for cancer patients. Since discrete EHR-imbedded algorithms drive defining aspects of the intervention, the approach can be efficiently disseminated and updated by specifying and modifying these centralized EHR algorithms.