The purposes of this study are to analyze the groundwater quality of the Ogallala Aquifer and evaluate the hydrological characteristics in the southern High Plains region of the Permian Basin, Texas. Levels of chloride, fluoride, nitrate, selenium, pH, and total dissolved solids (TDS) were analyzed for the period 1990–2016. Data concerning a total of 133 wells were collected from the Texas Water Development Board (TWDB), which is an open database provided by the US government. The average levels of contaminants were compared to their respective Maximum Contaminant Levels (MCL) stipulated by the Environmental Protection Agency (EPA). The study area experienced high concentrations of most parameters including chloride, fluoride, nitrate, selenium, and TDS, within the contaminants’ respective MCLs. Borden and Dawson counties experienced the highest overall amounts of groundwater pollutants. Possible sources of each contaminant are discussed, with oil and gas activities, agricultural practices, and other human actions impacting the conditions. This research provides important information about groundwater quality of the Ogallala Aquifer and contributes to understanding the response to development in the Permian Basin, Texas.