BACKGROUND: Video games have rapidly become mainstream in recent decades, with over half of the US population involved in some form of digital gaming. However, concerns regarding the potential harms of excessive, disordered gaming have also risen. Internet gaming disorder (IGD) has been proposed as a tentative psychiatric disorder that requires further study by the American Psychological Association (APA) and is recognized as a behavioral addiction by the World Health Organization. Substance use among gamers has also become a concern, with caffeinated or energy drinks and prescription stimulants commonly used for performance enhancement. OBJECTIVE: This study aimed to identify substance use patterns and health-related concerns among gamers among a population of Reddit users. METHODS: We used the public streaming Reddit application programming interface to collect and analyze all posts from the popular subreddit, r/StopGaming. From this corpus of posts, we filtered the dataset for keywords associated with common substances that may be used to enhance gaming performance. We then applied an inductive coding approach to characterize substance use behaviors, gaming genres, and physical and mental health concerns. Potential disordered gaming behavior was also identified using the tentative IGD guidelines proposed by the APA. A chi-square test of independence was used to assess the association between gaming disorder and substance use characteristics, and multivariable logistic regression was used to analyze whether mental health discussion or the mention of any substance with sufficient sample size was significantly associated with IGD. RESULTS: In total, 10,551 posts were collected from Reddit from June 2017 to December 2022. After filtering the dataset for substance-related keywords, 1057 were included for further analysis, of which 286 mentioned both gaming and the use of ≥1 substances. Among the 286 posts that discussed both gaming and substance use, the most mentioned substances were alcohol (n=132), cannabis (n=104), and nicotine (n=48), while the most mentioned genres were role-playing games (n=120), shooters (n=90), and multiplayer online battle arenas (n=43). Self-reported behavior that aligned with the tentative guidelines for IGD was identified in 66.8% (191/286) posts. More than half, 62.9% (180/286) of the posts, discussed a health issue, with the majority (n=144) cited mental health concerns. Common mental health concerns discussed were depression and anxiety. There was a significant association between IGD and substance use (P<.001; chi-square test), and there were significantly increased odds of IGD among those who self-reported substance use (odds ratio 2.29, P<.001) and those who discussed mental health (odds ratio 1.64, P<.03). CONCLUSIONS: As gaming increasingly becomes highly prevalent among various age groups and demographics, a better understanding of the interplay and convergence among disordered gaming, substance use, and negative health impacts can inform the development of interventions to mitigate risks and promote healthier gaming habits.