Background Medically unexplained symptoms (MUS) constitute a major health problem because of their high prevalence, the suffering and disability they cause, and the associated medical costs. Web-based interventions may provide an accessible and convenient tool for managing MUS. We developed a personalized, Web-based, guided self-help intervention for MUS in primary care (Grip self-help) and would compare its effectiveness with that of usual care. Objective This paper aims to describe the rationale, objectives, and design of a pragmatic randomized controlled trial (RCT) assessing the effectiveness of Grip self-help. Methods For a pragmatic multicenter RCT, 165 adult patients with mild to moderate MUS will be recruited through general practices in the Netherlands. Randomization will be performed at general practice level. Over the course of several months, patients in the intervention group will receive a personalized set of Web-based self-help exercises, targeting the unhelpful cognitions, emotions, behaviors, and social factors that are relevant to them. The intervention is guided by a general practice mental health worker. The control group will receive care-as-usual. Primary outcome is physical health-related quality of life (RAND-36 or 36-item general health survey, physical component score). Secondary outcomes include severity of physical and psychological symptoms, mental health–related quality of life, cost-effectiveness, and acceptability. Assessments will take place at baseline, end of treatment, and at 16-, 26-, and 52-week follow-ups. Results Recruitment started in December 2018, and enrolment is ongoing. The first results are expected to be submitted for publication in December 2021. Conclusions To our knowledge, this is the first study to combine the concepts of electronic health, self-help, and personalized medicine in the treatment of MUS. By improving the quality of life and reducing symptoms of patients with MUS, Grip self-help has the potential to reduce costs and conserve scarce health care resources. Trial Registration Dutch Trial Register NTR7390; https://www.trialregister.nl/trial/7390. International Registered Report Identifier (IRRID) PRR1-10.2196/13738