Large rivers act as essential arteries linking land and ocean, integrating the environmental dynamics of entire watersheds. The rapid climate warming in the Arctic region has altered a series of environmental processes and could reasonably be expected to modify the dynamics of carbon and nutrients. Here, we analyzed carbon, nitrogen, and phosphorus dynamics within the Mackenzie River watershed from 2000 to 2023, based on the water flow and quality data from the principal rivers within the basin. Our results indicate that while the discharge and total organic carbon (TOC) flux to the Arctic Ocean stayed relatively constant over the 24-year period, there were notable changes in TOC composition. Specifically, the proportion of particulate organic carbon (POC) rose from 27% to 46%. Additionally, the flux of dissolved organic carbon (DOC) increased in low-latitude sub-basins without permafrost coverage but decreased in high-latitude areas. The flux of total dissolved nitrogen (TDN) has increased particularly at the river discharge to the Arctic Ocean, whereas total phosphorus (TP) exhibited a widespread decline across the entire watershed. The varied responses among these species indicate that biogeochemical cycles in the Arctic region are controlled by complex interactions of multiple processes and are highly reliant on the characteristics of sub-basins. Comparing the input and output carbon and nutrients loadings of large lakes in the basin suggests intensified metabolism within these lakes. The findings of this study will enhance understanding of Pan-Arctic ecosystem functions and help fill the gap in the carbon and nutrient budgets in this region.