Amid a proliferation of highly potent opioids, school systems have sought to invest in programs for preventing substance misuse. School teams often prioritize early screening and intervention to prevent student substance misuse; however, given the limited resources of many schools, it is crucial to understand the extent to which commonly available data and existing frameworks are relevant for prevention efforts. In this study, we examined (a) how commonly available data on substance misuse (office discipline referrals [ODRs]) relate to self-reported substance misuse and (b) how positive behavioral interventions and supports (PBIS) implementation across tiers relates to these substance-related outcomes. We found that self-reported substance misuse is significantly related to substance-related ODRs, but that self-report rates are much higher than ODR rates. We also found that Tier 2 PBIS implementation was associated with significantly lower rates of both self-reported substance misuse and substance-related ODRs. These findings suggest that aspects of PBIS implementation could be beneficial in preventing substance misuse, but more research is needed to understand what specific school-based practices best address these student behavioral health needs.