Conventional hydrologic model calibration approaches focus on the accurate simulation of streamflow, disregarding internal process simulations. Stable isotope tracers can provide additional information on water sources, fluxes, and storages, which can be used to inform hydrologic model calibration. This study assesses the value of adding isotope data to model calibration and evaluates the relative merit of isotope simulation performance metrics for the purposes of hydrological model calibration. Isotope-enabled calibrations were tested for a process-based model (isoWATFLOOD) of the Athabasca watershed (150 000 km2) in northern Alberta and Saskatchewan, including global sensitivity analyses, Monte Carlo simulations, and multi-objective optimizations. Using isotope tracer data in calibration is found to improve both process and streamflow component identifiability. Optimizing both flow and isotope simulation performance produces better flow simulation ensembles, with improved observation capture and validation performance, relative to optimizing flow simulations alone. Overall, including isotope tracer simulation performance in calibration led to more robust streamflow modeling, even in a mesoscale watershed with limited isotope observation datasets.