A multidisciplinary and integrated study comprising hydrogeology, hydrochemistry, environmental isotopes, and numerical flow modeling has been carried out in the part of the Upper Thal Doab, Indus Basin (Pakistan) to understand the mechanism of the groundwater flow system, its suitability for municipal and agriculture use, surfacewater-groundwater interaction, recharge mechanism and determination of groundwater residence time. The study area lies in the province of Punjab and it is mainly consisted of Layyah district and some parts of Bhakkar, Muzaffargarh and Jhang districts. It is bounded on the west by the River Indus and on the east by the Jhelum and Chenab rivers. Hydrogeological data collected from various sources has been utilized effectively with the support of NeuraDB and PPDM, and efficient workflows that were developed in MS Visio software. Spatial analysis and thematic mapping of the study area have been carried out using ESRI ArcGIS software. Twenty four (24) groundwater samples have been collected from the water table surfaces and also beneath them at every 3.3 m (10 ft) intervals, which were analyzed for major cations (Na+, Ca2+, Mg2+, K+) and anions (HCO3 -, Cl-, and SO4 2-) to evaluate the groundwater quality for municipal and agriculture use. Different irrigation indices including Sodium Adsorption Ratio (SAR), Percent Sodium (%Na), Residual Sodium Bicarbonate (RSBC), Kelly’s Index (KI), Permeability Index (PI) and Potential Soil Salinity (PS) have been evaluated for classification and suitability of groundwater to be used for irrigation purposes. Chemically analyzed data is projected graphically on variety of plots including Piper, Durov, Ternary, Schoeller, Series plots, Wilcox, Depth Profile, Radial, Stiff, and Pie charts with respect to the various depths of 50, 100, 150, 200, 250 and 300 m. Thematic maps constructed (at the depth of 200 m) in GIS are used to evaluate the overall trend and better understanding of the study area. This study infers different water types in the Upper Thal Doab; most of them belong to water type of Na-Cl or K-HCO3. Other predominant hydrogeochemical facies are Na-SO4, K-SO4, Mg-Cl, K-Cl, Na-HCO3, Mg-HCO3, Mg-SO4. Electrical conductivity (EC) has shown a direct relationship with Sodium (Na+) and Total Dissolved Solids (TDS) at various depths. Most of the samples indicate medium to very high ii salinity hazard based on TDS, EC, MAR, %Na and KI, and are thus considered unsuitable for irrigation purposes. Fifty eight (58) samples were used for stable isotopes (δ18O and δ2H) and forty three (43) for radioactive isotopes (3H) to analyze surfacewater-groundwater interaction, study of recharge mechanism and determination of residence time (age) of groundwater. The sampling points included rivers, canals, hand pumps and tube wells (water wells). The rivers and canals represent surface water (recharge source) while the hand pumps and tube wells represent the shallow and deep groundwater respectively. This study yielded that groundwater is recharged mainly by Indus Basin Irrigation System (IBIS) and rainfall. Furthermore, younger waters are available along the Indus and Chenab Rivers up to greater depth and large areal extent. Numerical groundwater flow modeling has been conducted using FEFLOW and run for both steady-state and transient conditions. The steady-state model was calibrated with the hydrogeological conditions of December 2002 when water levels in the aquifer were nearly in equilibrium. The Parameter Estimation (PEST) program was used for the automatic calibration. The calibrated model was used further to visualize the future groundwater behavior for the next 25 years as a predictive tool to quantify the potential impacts of specific stresses on potentiometric heads and other model outputs over a period of time. Numerical groundwater modeling shows that surrounding rivers (Indus and Chenab) and major irrigation canals along with their distributaries are the major sources of groundwater recharge and responsible for any groundwater level changes in the area. These developed models used as effective tools for evaluating better management options for sustainable use of groundwater. Integration of GIS with groundwater modeling provided an efficient way of analyzing and monitoring groundwater. Different software including, AquaChem, AqQA, NeuraDB, MS Visio and ArcGIS were used as an additive tool to develop supportive data for numerical groundwater modeling, analyzing hydrochemical and isotopes data, managing groundwater data, integration and presentation of modeling results. The overall results demonstrate that the application of GIS in conjunction with hydrochemical analysis, isotopic study and numerical groundwater flow modeling provided an excellent and powerful tool to study groundwater resources and design suitable exploration and management schemes.