Release of arsenic (As) and fluoride (F-) species into groundwater is a serious health concern around the world. The present study was the first systematic baseline study conducted in Rahim Yar Khan district, Punjab, focusing on As and F- contamination in groundwater. A total of 51 representative groundwater samples comprising of 44 samples from agricultural suburbs and 7 from an industrial base were analysed. Statistical parameters, principal component analysis-multiple linear regression (PCA-MLR) and health risk assessment model were used to investigate the hydro geochemistry, spatial patterns, interrelation, source contribution and associated health risks of high As and F- in groundwater of the study area. Results showed high risk of F- exposure to people of the study area, with all samples exceeding the WHO standard of 1.5 mg/L, and for As, 32.5% of the studied groundwater samples exceeded the WHO standard (10 µg/L). The maximum As (107.23 µg/L) and F- (26.4 mg/L) levels were observed in samples close to the agricultural and smelting areas, implicating the frequent use of fertilizers and influence of industrial effluents in the study area. The PCA-MLR receptor model quantitatively illustrates that the majority of As and F- comes from natural sources, while, among anthropogenic sources, industrial and agricultural activities contributed the most. Health risk assessment revealed a high risk of As and F- contamination to the exposed population; therefore, detailed control strategies and policies are required in order to mitigate the health risks.