Purpose: Social media has propagated several “challenges” that engage primarily adolescents in life-threatening behaviors such as the “Benadryl Challenge,” where participants filmed themselves ingesting large doses of diphenhydramine. Once shared online, these activities have the potential to propagate, leading to an increase in those seeking emergency healthcare. Methods: This study correlated call volume from poison centers with online mentions of the Benadryl Challenge. Data was collected from the National Poison Data System (NPDS) and the RADARS® Web Monitoring Program across July 1 to December 31, 2020. The NPDS provided diphenhydramine-related call volume across poison centers and the RADARS® Web Monitoring Program estimated the total number of online mentions related to the Benadryl Challenge across online platforms, blogs, forums, and news websites. Analysis utilized cross-correlation statistics, identifying lead-lag relationships between the datasets. Results: Cross-correlation analysis revealed a reciprocal relationship with an increase in all diphenhydramine-related calls predicting a consistent but not statistically significant increase in web mentions. Following the first spike in web mentions was a statistically significant increase in adolescent-only related calls. The increase in poison center calls was consistently elevated over baseline for over 25 days following the spike in web mentions. Conclusions: Poison center call volume and web mentions demonstrate a reciprocal relationship and poison center call volume remained elevated for over 25 days after the spike in web mentions. Emergency services/departments and public health efforts can be informed real-time by these relationships as an early warning to healthcare facilities and professionals and may justify integration within these spaces to educate and prevent harm.