Background: Developmental disabilities are a set of heterogeneous delays or difficulties in one or more areas of neuropsychological development. Considering that childhood is an essential stage of brain development and developmental delays lead to personal or social burdens, the early detection of childhood developmental disabilities is important. However, early screening for developmental disabilities has been a challenge because of the fear of positive results, expensive tests, differences in diagnosis depending on examiners’ abilities, and difficulty in diagnosis arising from the need for long-term follow-up observation. Objective: This study aimed to assess the feasibility of using a serious game–derived index to identify heterogeneous developmental disabilities. This study also examines the correlation between the game-derived index and existing neuropsychological test results. Methods: The randomized clinical trial involved 48 children with either normal development or developmental disabilities. In this clinical trial, we used 19 features (6 from the Korean-Wechsler Preschool and Primary Scale of Intelligence, 8 from the Psychoeducational Profile Revised, 2 from the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, and 3 from the Pediatric Evaluation of Disability Inventory) from neuropsychological tests and 9 (7 Game Scores, Path Accuracy, and Completion Rate) from the serious game, DoBrain. The following analysis was conducted based on participants’ baseline information and neuropsychological test and game-derived index data for one week: (1) we compared the baseline information between the ND (Normal Development) and DD groups (Developmental Disabilities); (2) then we measured the correlation between the game-derived index and the neuropsychological test scores for each group; and (3) we built a classifier based on the game-derived index with a Gaussian process method and then compared the area under the curve (AUC) with a model based on neuropsychological test results. Results: A total of 16 children (ND=9; DD=7) were analyzed after selection. Their developmental abilities were assessed before they started to play the serious games, and statistically significant differences were found in both groups. Specifically, the ND group was more developed than the DD group in terms of social function, gross motor function, full-scale IQ, and visual motor imitation, in that order. Similarly, the ND group obtained a higher score on the game-derived index than the DD group. In the correlation analysis between the game-derived index and the neuropsychological tests, the ND group showed greater correlation with more variables than the DD group. The game-derived index–based model had an AUC=0.9, a similar detection value as the neuropsychological test-based model’s AUC=0.86. Conclusions: A game-derived index based on serious games can detect children with heterogenous developmental disabilities. This suggests that serious games can be used as a potential screening tool for developmental disabilities. Clinical Trial: Clinical Research Information Service KCT0003247; https://cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=12365

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