Polysubstance use is a highly prevalent public health issue, particularly among adolescents, and decisions on prevention programming and policies are often made at the local level. While there is a growing literature examining patterns of polysubstance use among adolescents, little is known about differences in those patterns across geographic regions. Using a large, representative sample of high school students from the state of Maryland (n = 41,091) from the 2018 Maryland Youth Risk Behavior Survey, we conducted a latent class analysis (LCA) of adolescent substance use along nine binary indicators, including past 30-day combustible tobacco, e-cigarette, alcohol, and cannabis use, as well as lifetime use of prescription opioids, cocaine, heroin, methamphetamine, and injection drug use. Measurement invariance across counties was examined using the Multiple Indicators and Multiple Causes (MIMIC) procedure. The results of the LCA show three classes of adolescent substance use for the total sample: (1) low substance use, (2) commonly used substances (i.e., e-cigarette, alcohol, and cannabis use), and (3) polysubstance use. The results from the MIMIC procedure demonstrated geographic differences in students' endorsement of specific indicators and their class membership. These differences demonstrate the need for an examination of local trends in adolescent polysubstance use to inform multi-tiered prevention programming and policy.