We investigate changes in the ocean circulation due to the variation of isopycnal diffusivity (k(iso)) in a global non-eddy-resolving model. Although isopycnal diffusion is thought to have minor effects on interior density gradients, the model circulation shows a surprisingly large sensitivity to the changes: with increasing k(iso), the strength of the Atlantic residual overturning circulation (AMOC) and the Antarctic Circumpolar Current (ACC) transport weaken. At high latitudes, the isopycnal diffusion diffuses temperature and salinity upward and poleward, and at low latitudes downward close to the surface. Increasing isopycnal diffusivity increases the meridional isopycnal fluxes whose meridional gradient is equatorward, hence leading to a negative contribution to the flux divergence in the tracer equations and predominant cooling and freshening equatorward of 40 degrees. The effect on temperature overcompensates the countering effect of salinity diffusion, such that the meridional density differences decrease, along with which ACC and AMOC decrease. We diagnose the adjustment process to the new equilibrium with increased isopycnal diffusion to assess how the other terms in the tracer equations react to the increased k(iso). It reveals that around +/- 40 degrees latitude, the cooling induced by the increased isopycnal flux is only partly compensated by warming by advection, explaining the net cooling. Overall, the results emphasize the importance of isopycnal diffusion on ocean circulation and dynamics, and hence the necessity of its careful representation in models. SIGNIFICANCE STATEMENT: The effect of mixing by mesoscale eddies, represented as diffusion along surfaces of constant density in models, on the ocean circulation is not well understood. Here, we show that an increase in the eddy diffusivity in different setups of a global ocean model leads to a surprisingly large change of the ocean circulation. The strength of the Atlantic overturning circulation and the Antarctic Circumpolar Current decrease. We find that the interior ocean becomes cooler and fresher and that the temperature effect on density dominates over salinity, resulting in a decrease in the density gradients. Our results point out the importance of eddy diffusion on ocean circulation, and hence the necessity of its correct representation in ocean and climate models.