Background Persons with mild to borderline intellectual disabilities generally show dysfunctions in mentalization and stress regulation, resulting in problematic social relationships and personal distress. Intervention programs may improve mentalizing abilities. The aim of this study is to examine the effectiveness of the serious game ‘You & I’ in changing mentalizing abilities and stress regulation in adults with mild to borderline intellectual disabilities. Methods A two-arm, parallel, superiority randomized controlled trial will be used with 172 adults with mild to borderline intellectual disabilities. Participants will be randomly assigned to either the experimental group to play the serious game ‘You & I’ or a waitlist control group. Participants will be assessed at baseline, post intervention (5 weeks after baseline), and follow-up (6–8 weeks after post intervention). They also will fill in questionnaires for personal factors, personal development, personal well-being, social validity, autism spectrum quotient (demographic variables), mentalizing abilities (primary outcome measure), and stress regulation (secondary outcome measure). Discussion The serious game ‘You & I’ aims to improve mentalizing abilities in adults with mild to borderline intellectual disabilities, which is expected to lead to improved regulation of stress in social relationships. The study’s unique feature is the use of a serious game to improve mentalizing abilities. If the intervention is effective, the serious game can be implemented on a broad scale in Dutch care organizations for people with intellectual disabilities as an effective preventive tool to improve mentalizing abilities. Trial registration Netherlands Trial Register, NTR7418 . Registered on 2 August 2018. Electronic supplementary material The online version of this article (10.1186/s13063-019-3608-9) contains supplementary material, which is available to authorized users.