Background Patients’ implicit attitudes toward medication need and concerns may influence their adherence. Targeting these implicit attitudes by combining game-entertainment with medication-related triggers might improve medication adherence in patients with rheumatoid arthritis (RA). Objective The aim of this study was to describe the systematic development of a serious game to enhance adherence to antirheumatic drugs by using intervention mapping. Methods A serious game was developed using the intervention mapping framework guided by a multidisciplinary expert group, which proceeded along 6 steps: (1) exploring the problem by assessing the relationship between medication adherence and implicit attitudes, (2) defining change objectives, (3) selecting evidence-based behavior change techniques that focused on adjusting implicit attitudes, (4) designing the intervention, (5) guaranteeing implementation by focusing on intrinsic motivation, and (6) planning a scientific evaluation. Results Based on the problem assessment and guided by the Dual-Attitude Model, implicit negative and illness-related attitudes of patients with RA were defined as the main target for the intervention. Consequently, the change objective was “after the intervention, participants have a more positive attitude toward antirheumatic drugs.” Attention bias modification, evaluative conditioning, and goal priming were the techniques chosen to implicitly target medication needs. These techniques were redesigned into medication-related triggers and built in the serious puzzle game. Thirty-seven patients with RA tested the game at several stages. Intrinsic motivation was led by the self-determination theory and addressed the 3 needs, that is, competence, autonomy, and relatedness. The intervention will be evaluated in a randomized clinical trial that assesses the effect of playing the serious game on antirheumatic drug adherence. Conclusions We systematically developed a serious game app to enhance adherence to antirheumatic drugs among patients with RA by using the intervention mapping framework. This paper could serve as a guideline for other health care providers when developing similar interventions.