In recent years, remote sensing data have revealed considerable potential in unraveling crucial information regarding water balance dynamics due to their unique spatiotemporal distribution characteristics, thereby advancing multi-objective optimization algorithms in hydrological model parameter calibration. However, existing optimization frameworks based on the Soil and Water Assessment Tool (SWAT) primarily focus on single-objective or multiple-objective (i.e., two or three objective functions), lacking an open, efficient, and flexible framework to integrate many-objective (i.e., four or more objective functions) optimization algorithms to satisfy the growing demands of complex hydrological systems. This study addresses this gap by designing and implementing a multi-objective optimization framework, Py-SWAT-U-NSGA-III, which integrates the Unified Non-dominated Sorting Genetic Algorithm III (U-NSGA-III). Built on the SWAT model, this framework supports a broad range of optimization problems, from single- to many-objective. Developed within a Python environment, the SWAT model modules are integrated with the Pymoo library to construct a U-NSGA-III algorithm-based optimization framework. This framework accommodates various calibration schemes, including multi-site, multi-variable, and multi-objective functions. Additionally, it incorporates sensitivity analysis and post-processing modules to shed insights into model behavior and evaluate optimization results. The framework supports multi-core parallel processing to enhance efficiency. The framework was tested in the Meijiang River Basin in southern China, using daily streamflow data and Penman–Monteith–Leuning Version 2 (PML-V2(China)) remote sensing evapotranspiration (ET) data for sensitivity analysis and parallel efficiency evaluation. Three case studies demonstrated its effectiveness in optimizing complex hydrological models, with multi-core processing achieving a speedup of up to 8.95 despite I/O bottlenecks. Py-SWAT-U-NSGA-III provides an open, efficient, and flexible tool for the hydrological community that strives to facilitate the application and advancement of multi-objective optimization in hydrological modeling.