The coordinated interference of multiple human activities is the main factor leading to the degradation of coastal ecosystems, and knowledge of its impact mechanism is the scientific basis for implementing adaptive management. The Regional Ocean Modeling Systems (ROMS) coupled with Carbon, Silicate and Nitrogen Ecosystem (CoSiNE) was used to construct a coastal ecosystem model coupling multiple human activities, including runoff discharge, reclamation, mariculture, and atmospheric deposition. The model performance was comprehensively evaluated in the Bohai Sea as the research area. Moreover, multiple scenarios of human activities were designed based on orthogonal experiments, and the contribution rate of multiple human activities on marine ecological factors was explored through scenario simulation and variance analysis. The results showed that (1) the simulated results were generally in accordance with the observations. In the past 40 years, the Bohai Sea had a regime shift from an N-limited oligotrophic state to a P-limited eutrophic state. (2) The results of the orthogonal experiment indicated that for DIN changes, the contribution rate of multiple human disturbances was ranked as follows: runoff discharge> atmospheric deposition> mariculture> reclamation. The ranking of DIP was runoff discharge> mariculture> reclamation> atmospheric deposition. The ranking of nitrogen content in plankton was runoff discharge> reclamation> atmospheric deposition> mariculture. (3) The response of different ecological factors in the Bohai Sea to different human activities showed spatial heterogeneity. The impact of runoff discharge, reclamation and mariculture on the Bohai Sea ecosystem decreased with distance from the coastline, while the impact of atmospheric deposition was relatively uniform. The model established by this study not only has convenient scenario simulation, but also has high accuracy, which can be used for quantitative research on the synergistic effects of multiple human activities, with good prospects in simulating coastal ecosystems with strong human interference.