Abstract Background Problematic Internet gaming is an increasingly recognized global mental health problem. This multicultural cross-sectional study examined the association between Internet gaming disorder (IGD) symptoms and anxiety and depressive symptoms and substance use within a sample of young Internet users. In total, 3529 college/university students (1260 (35.7%) males; mean age 21 ± 3 years) were surveyed online. We assessed online gaming patterns using the Internet Gaming Disorder Self-report for College/University Students (ICMH-IGD), symptoms of depression using the Patient Health Questionnaire-9, and symptoms of anxiety using the Generalized Anxiety Disorder scale-7. Results IGD symptoms were associated with symptoms of depression, anxiety, and substance use, independent of time spent online, psychiatric diagnosis, culture, or sociodemographic characteristics. For males, more significant IGD symptoms were associated with more extended Internet browsing per day time and higher levels of anxiety and depressive symptoms, while for females, with more extended Internet browsing per day time, marihuana use, and higher levels of depressive symptoms. Conclusions Our study found that more overt symptoms of IGD were associated with higher levels of anxiety and depressive symptoms and substance use. Still, these associations differed among males and females, suggesting that gender differences should be considered when planning specific treatments.