The transboundary Milk River Aquifer (MRA) across southern Alberta (Canada) and northern Montana (USA), faces increasing water demand and extreme events such as droughts, underscoring the need for improved understanding of groundwater quality evolution. Previous studies inadequately explained spatial variations in major ion chemistry with groundwater flow distance, direction and age. The objective of this study is to propose a process-based hydro-geochemical model that quantifies major geochemical processes controlling groundwater quality. We integrated 774 quality-controlled groundwater samples from 549 wells along with 20 newly collected samples for age-dating (14C, 36Cl, 81Kr) purposes. Inverse PHREEQC modeling combined with multi-isotope analysis (δ¹⁸OWater-δ²HWater, δ¹³CDIC, δ³⁴SSulphate-δ¹⁸OSulphate, δ¹³CMethane- δ²HMethane) identified four hydrogeochemical zones explaining carbonate buffering, cation exchange and pyrite oxidation near recharge zone (<50 km), while bacterial sulphate reduction and methanogenesis in distal zones (>75 km). Zone 1 (<25 km) has freshly recharged Ca-Mg-HCO3 groundwater which rapidly changes to young (<65 kyr) Na-HCO3-SO4 groundwater (Na+ ~700 mg/l, SO₄²⁻ ~800 mg/l, HCO₃⁻ ~400 mg/l) from pyrite oxidation. Zone 2 (25-75 km) has older (65-150 kyr) Na-HCO3-SO4 water with low Ca²⁺ and Mg²⁺ (<10 mg/L), elevated (Na+ ~800 mg/l, SO₄²⁻ ~1000 mg/l, HCO₃⁻ ~700 mg/l) with progressive cation exchange. Zone 3 (75-100 km) exhibits older (150-350 kyr) Na-HCO₃ composition with organic matter oxidation (δ¹³CDIC -22‰), sulphate reduction (SO₄²⁻ <50 mg/L, δ³⁴SSulphate +10 to +15‰), and methanogenesis initiation (CH₄ 30-60 mg/L,δ¹³CMethane -78 to -68‰). Zone 4 (>100 km) represents oldest (350-500 kyr) and most evolved Na-Cl groundwater (Na⁺ ~1000 mg/L, Cl⁻ ~150 mg/L) with ongoing methanogenesis.