Recent research has suggested that people with autism spectrum disorder may be disproportionately at risk of substance use disorders. This study analyzed national-level Medicaid Claims data to compare substance use disorder prevalence among Medicaid enrollees with autism spectrum disorder (N = 388,426) and a random sample of enrollees without autism spectrum disorder (n = 745,699) and to examine whether this association differs across sex and age groups and changes after adjusting for co-occurring mental health conditions. We also examined how the association between autism spectrum disorder and substance use disorder is moderated by co-occurring non-autism spectrum disorder mental health conditions and by community-level social determinants of health by merging Medicaid Claims data with zip code-level US Census data on socioeconomic deprivation. By 2016, 7% of Medicaid beneficiaries with autism spectrum disorder and no intellectual disability had at least one substance use disorder diagnosis, up from 1.75% USD prevalence among enrollees with autism spectrum disorder (no intellectual disability) in 2012 Medicaid data. Individuals with autism spectrum disorder aged 30-64 years were at an elevated risk of cannabis and hallucinogen disorders; this risk is likely compounded by co-occurring mental health conditions, which affect a half of all individuals with autism spectrum disorder and only 23% of individuals without autism spectrum disorder. Research and policy implications are discussed in turn.