Deep groundwater characteristics provide valuable information on oil and gas extraction and evolution of hydrosphere, and nonmetallic and metallic elements in deep groundwater are raising industrial interest. There is therefore a need for a better understanding of the origin and evolution of deep groundwater in large sedimentary basins, e.g., by using non-traditional isotopes. Here, we review the constraints of isotopes of chloride (Cl), bromine (Br), boron (B), lithium (Li), helium (He), neon (Ne), and argon (Ar) on the origin and evolution of deep groundwater in large sedimentary basins. In deep groundwater, δ 37 Cl ranges from −1.96 to + 2.07‰, δ 81 Br from −1.50 to + 3.35‰, δ 11 B from + 1.10 to + 39.99‰, and δ 7 Li from −1.00 to + 31.80‰. These values either overlap or are different compared to those in freshwater, e.g., meteoric water, river water and shallow groundwater, hydrothermal fluid, seawater, subsurface brine, lake sediment, or mineral. Noble gas isotopes such as 3 He/ 4 He, 4 He/ 20 Ne, and 36 Ar/ 40 Ar are also effective tracers for deep groundwater evolution. Integrating multiple nontraditional isotopes allows to study dissolution, sedimentation, evaporation, and mixing of different waters in deep aquifers.