The dramatic rise in Oklahoma seismicity since 2009 is due to wastewater injection. The role of injection depth is an open, complex issue, yet critical for hazard assessment and regulation. We developed an advanced Bayesian Network to model joint conditional dependencies between spatial, operational, and seismicity parameters. We found injection depth relative to crystalline basement most strongly correlates with seismic moment release. The joint effects of depth and volume are critical, as injection rate becomes more influential near the basement interface. Restricting injection depths to 200–500 m above basement could reduce annual seismic moment release by a factor of 1.4–2.8. Our approach enables identification of sub-regions where targeted regulation may mitigate effects of induced earthquakes, aiding operators and regulators in wastewater disposal regions.