The groundwater quality of Punjab, India is of huge concern owing to the presence of various toxic contaminants that includes uranium and other trace elements. The focus of this study is to identify the hydrogeochemical processes responsible for uranium mobilization in groundwater and evaluation of groundwater quality in uranium contaminated zones for drinking, irrigation use along with associated health risks. The study was conducted using the water quality data obtained from 302 sampling locations covering the entire state of Punjab reported by Central Ground Water Board between 2019 and 2020. It was observed that around 50% of the samples were exceeding the drinking water acceptable limits for total alkalinity, magnesium, pH, and Total Dissolved Solids. Around 25% of the samples were above drinking water acceptable limit for uranium in groundwater. A comprehensive multiplicative water quality index (MED-WQI) well represented the consolidated perspective of all individual water quality parameters wherein 40 sampling locations in districts viz. Bathinda, Fazilka, Ferozepur, Jalandhar, Kapurthala, Ludhiana, Muktsar and Sangrur fall under heavily-polluted water quality class due to high levels of uranium, alkalinity, and hardness. The Piper plots and Gibbs diagram depicted that the majority of groundwater samples were characterized as Na+–HCO3−, Ca2+–Mg2+–HCO3− systems driven by rock-water interactions. Speciation analysis indicates that the dominant uranium species in groundwater of U-affected regions was primarily associated with calcium and alkalinity and exist in the form of CaUO2(CO3)32−, Ca2UO2(CO3)3(aq), UO2(CO3)34−, and UO2(OH)3−. Various irrigation indices depict that the groundwater in majority of the state, barring few districts in Malwa region, was suitable for irrigation. Further, a non-carcinogenic health risk assessment model showed association of high health risk with heavily-polluted water quality class. The results of this study would aid regulatory authorities in designing remedial strategies and frame policy actions toward groundwater quality improvement in the uranium-affected regions of Punjab.