Anthropogenic activities and salinization are increasingly threatening groundwater resources, especially in arid and semi-arid regions. Unlike previous studies focusing on isotopes or hydrochemistry separately, this study investigates the first application of stable isotopes (water (delta 18OH(2)O and delta 2HH(2)O), dissolved nitrate (delta 15NNO(3) and delta 18ONO(3)) and sulfate (delta 34SSO(4) and delta 18OSO(4))), hydrochemical and statistical integrated approach to identify salinity and pollution sources in the Zeuss-Koutine (ZK) and Mio-Plio-Quaternary (MPQ) aquifers, Southeast of Tunisia. These techniques were combined to determine the water quality, recharge origin, salinity sources and potential sources of contamination, using 46 water samples collected from 40 exploitation wells and 6 wadis. The findings reveal that groundwater salinity and pollution is mainly controlled by evaporite dissolution and anthropogenic activities. Therefore, the electrical conductivity ranging from 1875 to 7090 mu S/cm at 25 degrees C. All samples are above the WHO-recommended tolerable limits for sulfate, chloride, sodium, and fluoride. The hazard quotients (HQ) for non-carcinogenic health risk assessment indicate that children are the most vulnerable to fluoride exposure. Nitrate concentrations ranged from 1 mg/L to 120.4 mg/L and 35% of samples surpassed the WHO standard for drinking water. delta 15NNO(3) (varied from + 6.2 to + 12.3 parts per thousand) and delta 18ONO(3) indicates an origin from nitrogen fertilizers in rural areas and from wastewater in some samples located near urban and industrial areas and organic nitrate (manure) affected by denitrification process. Based on delta 18OH(2)O and delta 2HH(2)O, most of the ZK and MPQ samples have a local meteoric origin with an evaporation process. The relationship between high nitrate concentrations and isotopic composition confirms the irrigation return flow process. delta 34SSO(4) (ranged from + 11.7 to + 14.4 parts per thousand) and delta 18OSO(4) indicates that sulfate is derived mainly from natural interaction with geogenic Triassic evaporites. Some samples show an origin from inorganic fertilizers and sewage. Statistical analysis confirms results and indicates the existence of two major groups of samples affected by natural evaporite dissolution and anthropogenic inputs such as agricultural fertilizers and wastewater. The integrated approach provides valuable insights in distinguishing natural from anthropogenic influences in semi-arid aquifers, emphasizes the urgent need to develop sustainable groundwater management in southeastern Tunisia and highlights the importance of long-term monitoring of groundwater quality.Graphical AbstractThis graphical abstract provides a visual summary of the anthropogenic impacts on groundwater quality using hydrochemistry, isotopes (water (delta 18OH(2)O and delta 2HH(2)O), dissolved nitrate (delta 15NNO(3) and delta 18ONO(3)) and sulfate (delta 34SSO(4) and delta 18OSO(4))) and statistical methods in the Zeuss-Koutine (ZK) and Mio-Plio-Quaternary (MPQ) aquifers, Southeastern Tunisia. The geographical map shows the ZK, MPQ and surface samples repartition across the study area (46 water samples). Physicochemical parameters and isotopic analysis are performed. Piper diagrams reveal the existence of three major water groups: Na-Ca/SO4-Cl for ZK samples, Na-Ca-Mg/SO4-Cl wand Ca-Mg/SO4 for MPQ samples. delta 18OH(2)O vs. delta 2HH(2)O diagram indicates the meteoric origin of groundwater recharge. delta 15NNO(3) vs. delta 18ONO(3) shows the existence of a denitrification process and identifies fertilizers and wastewater as main source of nitrate pollution. Based on delta 34SSO(4) vs. delta 18OSO(4) diagram, the Triassic evaporites are the main source of dissolved sulfate on groundwater. Correlation heat maps and PCA reveal that the groundwater salinity is governed by natural processes such as seawater intrusion, evaporation, and evaporite dissolution, while isotopic signatures and nitrate-related parameters reveal significant anthropogenic contributions, particularly from agricultural and urban sources.