Background: High cannabis use rates among American Indian (AI) adolescents necessitate the identification of factors that protect against early cannabis initiation. Methods: Data collected from 279 AI middle school students attending reservation-based schools in 2018 and 2019 were analyzed. Three waves of data, with approximately 6 months between each, were used. A repeated measures latent class analysis examined a school-related protective factor index over three waves. The predictive power of lifetime cannabis use on school protection class membership was estimated, along with differences in past month cannabis use at follow-up 2 across school protection classes while holding baseline use constant. Results: Four school protection classes were identified: high, moderate, low, and declining protection. Abstinence at baseline was associated with an increased odds of membership in the high protection class compared to the moderate and low protection classes. Students with consistent and high school protection throughout middle school were significantly less likely to report past month cannabis use at follow-up 2 compared to other classes. Implications for School Health Policy, Practice, and Equity: Maintaining a high level of school protection throughout middle school substantially lowers the odds of cannabis use among AI adolescents. Conclusions: Interventions to promote school-related protective factors in this population are essential and should be designed and tested.