Deep geothermal energy represents an essential component of the future energy supply because the resources greatly exceed the demand, and the base load capability can compensate for temporal fluctuations in wind and solar power. By far, the largest amount of heat is contained in the crystalline basement, accessible almost everywhere through deep drilling. An interdisciplinary approach for a techno-economic resource assessment was applied to provide stakeholders with a more reliable basis for decision-making in the Northern Upper Rhine Graben. This approach incorporated data from various sources such as boreholes, outcrops, geophysical surveys, geomechanical models, and operating geothermal power plants. Emphasis was placed on resources tied to large-scale fault zones, exhibiting preferential hydraulic properties. Uncertainties in the calculations were quantified using Monte Carlo simulations. The resource base in the basement of the Northern Upper Rhine Graben is about 830 PWhth, of which about 8.2–16.1 PWhth could potentially be extracted with current technologies in enhanced geothermal systems. A comprehensive sensitivity analysis was carried out, examining the economic influence of nine parameters. Considering the reference power plant and the energy prices before the Ukraine war began in February 2022, the geothermal reserves are about 65% of the resources. However, given the massive recent increase in heat and electricity prices, a higher percentage is also possible. Finally, a socio-economic-environmental assessment shows that in the Northern Upper Rhine Graben, geothermal resources largely coincide with favorable conditions at the surface, making the region a preferred target for geothermal utilization.