This study examined mediating effects of internal and external self-esteem on the relationship between components of parental monitoring and cannabis use among American Indian (AI) adolescents. A total of 4056 American Indian 7-12th grade students attending 42 schools on or near reservations completed the Our Youth, Our Future survey. The data were collected in 2018-2019 as part of an ongoing epidemiological, population-based study of AI youth. Exploratory and confirmatory factor analyses (EFA, CFA) of self-esteem were conducted, followed with mediation model testing. Four measures of parental monitoring were taken from the Parental Monitoring Short Scale (PMSS; total scale, parental knowledge, parental control, child disclosure/parental solicitation). The EFA and CFA results supported two factors of self-esteem: internal and external. All parental monitoring components related negatively to cannabis use. Additionally, all parental monitoring components were indirectly related to cannabis use through internal, but not external self-esteem. The results indicate that external self-esteem may not impact effects of parental monitoring on substance use among AI adolescents while internal self-esteem does. Further study of self-esteem interventions is indicated as potentially enhancing influences of parental monitoring on adolescent cannabis use along with other majority and ethnic minority adolescents to determine if these results extend beyond AI youth.