Introduction: Cognitive dysfunction is a hallmark feature of many psychiatric disorders. We aimed to study the prevalence and predictors of cognitive dysfunction (CD) among U.S. high school students and its association with time spent on digital devices. Methods: We performed a cross-sectional survey study using YRBSS 2019 data of U.S. high school students in grades 9–12. Cognitive dysfunction was defined by difficulties with remembering, concentrating, and making decisions due to emotional, physical, or mental problems. Digital screen time was described by daily time spent on TV, computers, tablets, and phone. We performed univariate and multivariable survey logistic regression analysis to identify the prevalence of cognitive dysfunction and its association with time spent on digital devices. Results: Out of 10,317 total participants, 3914 (37.9%) reported CD. The prevalence of CD was higher in females compared to males (46.0% vs. 29.9%). Compared to participants with no CD, participants with CD reported substance abuse, such as alcohol (35.8% vs. 26.6%), marijuana (28.3% vs. 17.6%), cigarette (8.1% vs. 4.7%), and illicit drugs (18.9% vs. 9.0%) and they reported a higher prevalence (p
< 0.0001 for all substances). Participants who felt sad and hopeless (62.8 vs. 22.1%) reported a high prevalence of CD, whereas participants with adequate sleep reported low prevalence (15.7% vs. 25.6%). In a regression, daily video game/internet use for non-work-related activities for 4 h (aOR:1.27; p
= 0.03) and ≥5 h (aOR:1.70; p
< 0.0001) demonstrated higher odds of CD, compared to participants with no daily use. Female sex, substance use, and depressed mood were additional predictors of CD. Conclusion: The prevalence of CD is high in U.S. high-school students. Female sex, substance abuse, depressed mood, and excessive VG/PC use is associated with high odds of cognitive dysfunction. Further research is needed to explore the complex relationship between screen time and cognitive dysfunction.