Injection of wastewater from unconventional oil development in the Midland Basin into strata between productive shales and crystalline basement totals more than 6 billion bbl between 2010 and 2023, with rates reaching more than 70 million bbl/month. This injection is associated with an increased rate of earthquakes in the upper basement, including more than 170 rate of local magnitude 3.0+ events. To understand how injection and subsequent pore pressure change (ΔPp) cause the earthquakes, we integrate earthquake occurrence with new fault interpretations, slip potential, and estimates of ΔPp from comprehensive geologic inputs to determine the injection rates and ΔPp thresholds associated with earthquake cluster onset. Local cluster onset is associated with ΔPp from 37 to 529 psi (0.26 to 3.65 MPa), with a mean of 216 psi (1.5 MPa) and a Pp gradient ranging from 0.458 to 0.555 psi/ft (0.010 to 0.012 MPa/m). Onset is associated with a variety of ΔPp histories, especially strong month-to-month ΔPp variability. There is a close spatiotemporal relationship between the rates of injection, ΔPp, change in critically stressed fault segment length, and seismicity. There is a loose coupling of +ΔPp and earthquake cluster development, but there is a temporally tight spatiotemporal coupling of −ΔPp and earthquake rate decrease. There is a distinct contrast in the rupture sensitivity of the fault systems as subject to ΔPp, with areas in the south and southwest (65–80 psi, 0.49–0.55 MPa) activated with smaller changes as compared to areas in the north (235 psi, 1.62 MPa). This indicates that dynamic injection capacity is inherently smaller in the south as compared to that in the north.