Alcohol and drug use are significant problems in the US and American Indian/Alaska Native (AI/AN) communities and individuals are known to be among the most affected. Alcohol and drug abuse are major causes of unintentional injury mortality, a cause group where rates have risen substantially over the 1999-2016 period with poisonings from opioids playing major role. We divided unintentional injuries into three groups; separating motor vehicle and poisoning deaths from all other cause types. Utilizing underlying cause mortality coded deaths we compared US rates for AI/AN and non-Hispanic white populations. Additionally, we considered rates in each of the 10 states with the largest numbers of AI/AN individuals to investigate state variability in rates, disparities and trends. Motor vehicle mortality had declining rates for both AI/AN and white groups, but a large disparity was maintained. Both groups showed a large drop in rates from 2006-10 around the recession. Conversely, poisoning mortality rates rose substantially in both groups and there was a large jump in AI/AN rates in 2008, resulting in an increased disparity that was maintained through 2016. For “All Other” unintentional injuries, higher rates were seen for AI/AN men especially at nearly double white rates, with AI/AN women about 40% higher. Rates were generally rising over the period, but there was a sharp decline in rates from 2005 to 2008 for AI/AN men and women and in 2007 for whites, after which the rise continues. Across the 10 states considered, rates varied substantially with lower rates in New York and Texas and higher rates in Alaska, Washington, Arizona and New Mexico. Results indicate substantial and persisting disparities in unintentional injury mortality reinforcing the need for alcohol and drug prevention efforts targeting AI/AN individuals and communities.