In nuclear fusion fuel cycle, the isotope separation system (ISS) and water detritiation system (WDS) are critical for recycling hydrogen isotopologues but have rarely been analyzed in an integrated manner. To address this gap, we developed a steady-state simulation program that explicitly integrated ISS and WDS using an equation-oriented framework, incorporating rigorous thermodynamic, column design, and hydrodynamic models for cryogenic distillation (CD) columns and a liquid-phase catalytic exchange (LPCE) column. Extensive parametric studies on key variables such as feed flowrates, tank composition, and column feed stages were conducted to analyze their impacts on the separation performance of WDS and tritium inventory within ISS, highlighting the interdependent characteristics arising from the changes of the neighboring system. Furthermore, we identified the suitable design and operating variable sets, balancing high detritiation performance with low tritium inventory by systematically varying both the interfacial and non-interfacial variables. By offering a rigorous steady-state simulation that enables a comprehensive analysis of the integrated ISS–WDS process, the significance of this work lies in the simulator’s potential to analyze both processes from an integrated perspective. As a result, such findings can be utilized to define safe and efficient interface conditions during their integrated operations.