Over 22 million Americans are current users of marijuana; half of US states allow medical marijuana, and several allow recreational marijuana. The objective of this study was to evaluate the impact marijuana has on hospitalizations, emergency department (ED) visits, and regional poison center (RPC) calls in Colorado, a medical and recreational marijuana state. This is a retrospective review using Colorado Hospital Association hospitalizations and ED visits with marijuana-related billing codes, and RPC marijuana exposure calls. Legalization of marijuana in Colorado has been associated with an increase in hospitalizations, ED visits, and RPC calls linked with marijuana exposure. From 2000 to 2015, hospitalization rates with marijuana-related billing codes increased from 274 to 593 per 100,000 hospitalizations in 2015. Overall, the prevalence of mental illness among ED visits with marijuana-related codes was five-fold higher (5.07, 95% CI: 5.0, 5.1) than the prevalence of mental illness without marijuana-related codes. RPC calls remained constant from 2000 through 2009. However, in 2010, after local medical marijuana policy liberalization, the number of marijuana exposure calls significantly increased from 42 to 93; in 2014, after recreational legalization, calls significantly increased by 79.7%, from 123 to 221 (p <0.0001). The age group <17 years old also had an increase in calls after 2014. As more states legalize marijuana, it is important to address public education and youth prevention, and understand the impact on mental health disorders. Improvements in data collection and surveillance methods are needed to more accurately evaluate the public health impact of marijuana legalization.