Groundwater contamination is a major concern in front of the scientific community because it is directly related to human health, especially in arid and semi-arid regions. Therefore, a comprehensive study was engaged to evaluate the water quality, potability, and human health risk assessment due to the consumption of fluoride- and nitrate-contaminated water in Jhunjhunu district of Rajasthan. In order to assess the water quality, samples were collected from 87 locations in the study region, and a total of 16 parameters were analyzed as per the standard methods. The results showed that the value of the number of quality parameters consisting of pH, EC, TDS, fluoride, chloride, nitrate, sulfate, total hardness, calcium, magnesium, and total alkalinity was higher than the recommended limit of BIS and WHO. The fluoride in 11% and nitrate in 6% of samples were observed to exceed the permissible limit of WHO. The results of risk assessment due to fluoride and nitrate revealed that hazard index values of 71% of groundwater samples for males, 78% of groundwater samples for females, and 75% of groundwater samples for children were greater than 1, indicating the significant health hazard due to consumption of groundwater. The water quality index (WQI) found that 39% of groundwater samples belong to categories that cannot be used for drinking purposes. Principal component analysis (PCA) reduced the large number of variables affecting the overall quality and chemistry of groundwater and determined four major components which account for 69.50% variance in the data. PCA concluded that both geogenic and anthropogenic sources of contamination influenced the groundwater of the study area.