We investigated how climate, rising atmospheric CO2 concentration, increasing anthropogenic nitrogen deposition and land use change influenced continental river flow over the period 1948–2004 using the Community Land Model version 4 (CLM4) with coupled river transfer model (RTM), a global river routing scheme. The model results indicate that the global mean river flow shows significant decreasing trend and climate forcing likely functions as the dominant controller of the downward trend during the study period. Nitrogen deposition and land use change account for about 5% and 2.5% of the decrease in simulated global scale river flow, respectively, while atmospheric CO2 accounts for an upward trend. However, the relative role of each driving factor is heterogeneous across regions in our simulations. The trend in river flow for the Amazon River basin is primarily explained by CO2, while land use change accounts for 27.4% of the downward trend in river flow for the Yangtze rive basin. Our simulations suggest that to better understand the trends of river flow, it is not only necessary to take into account the climate, but also to consider atmospheric composition, carbon-nitrogen interaction and land use change, particularly for regional scales.