Northwest India suffers from severe water scarcity issues due to a combination of over-exploitation and climate effects. Along with concerns over water availability, endemic water quality issues are critical and affect the usability of available water and potential human health risks. Here we present data from 243 groundwater wells, representing nine aquifer lithologies in 4 climate regions that were collected from the Northwestern Indian state of Rajasthan. Rajasthan is India’s largest state by area, and has a significant groundwater reliant population due to a general lack of surface water accessibility. We show that the groundwater, including water that is used for drinking without any treatment, contains multiple inorganic contaminants in levels that exceed both Indian and World Health Organization (WHO) drinking water guidelines. The most egregious of these violations were for fluoride, nitrate, and uranium; 76% of all water samples in this study had contaminants levels that exceed the WHO guidelines for at least one of these species. In addition, we show that much of the groundwater contains high concentrations of dissolved organic carbon (DOC) and halides, both of which are risk factors for the formation of disinfectant byproducts in waters that are treated with chemical disinfectants such as chlorine. By using geochemical and isotopic (oxygen, hydrogen, carbon, strontium, and boron isotopes) data, we show that the water quality issues derive from both geogenic (evapotranspiration, water-rock interactions) and anthropogenic (agriculture, domestic sewage) sources, though in some cases anthropogenic activities, such as infiltration of organic- and nitrate-rich water, may contribute to the persistence and enhanced mobilization of geogenic contaminants. The processes affecting Rajasthan’s groundwater quality are common in many other worldwide arid areas, and the lessons learned from evaluation of the mechanisms that affect the groundwater quality are universal and should be applied for other parts of the world.