The Earth system changed dramatically across the Eocene‐Oligocene Transition (EOT) on a variety of spatial and temporal scales. Understanding the many complex and interacting factors affecting the Earth's atmosphere and oceans at the EOT requires the combination of both data and modeling approaches and an understanding of the uncertainty in both of these elements. Here uncertainty in the Earth system response to various imposed forcings typical of changes at the EOT is assessed. By using an ensemble of simulations from the fully coupled general circulation model, HadCM3L, the uncertainty due to differences in the boundary conditions and insufficient model spin‐up is quantified. The surface temperature response in high‐latitude ocean regions, particularly where deep water formation occurs, is found to be highly sensitive to differences in boundary conditions (i.e., have the greatest magnitude of uncertainty), while low‐latitude oceans are the most insensitive to differences in boundary conditions (i.e., have the lowest magnitude of uncertainty). The length of spin‐up (or how far the model is from equilibrium) can have a significant effect on the response to some forcings and on the magnitude of uncertainty due to differences in boundary conditions. These findings are important to consider for future modeling work and for interpreting previous published simulations.