The present study discusses elevated groundwater arsenic (As) and fluoride (F(-)) concentrations in Mailsi, Punjab, Pakistan, and links these elevated concentrations to health risks for the local residents. The results indicate that groundwater samples of two areas of Mailsi, Punjab were severely contaminated with As (5.9-507 ppb) and F(-) (5.5-29.6 ppm), as these values exceeded the permissible limits of World Health Organization (10 ppb for As and 1.5 ppm for F(-)). The groundwater samples were categorized by redox state. The major process controlling the As levels in groundwater was the adsorption of As onto PO4 (3-) at high pH. High alkalinity and low Ca(2+) and Mg(2+) concentrations promoted the higher F(-) and As concentrations in the groundwater. A positive correlation was observed between F(-) and As concentrations (r = 0.37; n = 52) and other major ions found in the groundwater of the studied area. The mineral saturation indices calculated by PHREEQC 2.1 suggested that a majority of samples were oversaturated with calcite and fluorite, leading to the dissolution of fluoride minerals at alkaline pH. Local inhabitants exhibited arsenicosis and fluorosis after exposure to environmental concentration doses of As and F(-). Estimated daily intake (EDI) and target hazard quotient (THQ) highlighted the risk factors borne by local residents. Multivariate statistical analysis further revealed that both geologic origins and anthropogenic activities contributed to As and F(-) contamination in the groundwater. We propose that pollutants originate, in part, from coal combusted at brick factories, and agricultural activities. Once generated, these pollutants were mobilized by the alkaline nature of the groundwater.