A common approach for estimating the oceanic uptake of anthropogenic carbon dioxide (Canthro) depends on the linear approximation of oceanic dissolved inorganic carbon (DIC) from a suite of physical and biological ocean parameters. The extended multiple linear regression (eMLR) method assumes that baseline correlations and the resulting residual fields will remain constant with time even under the influence of secular climate changes. The validity of these assumptions over the 21st century is tested using a coupled carbon-climate model. Findings demonstrate that the influence of both changing climate and changing chemistry beyond 2–4 decades invalidates the assumption that the residual fields will remain constant resulting in significant errors in the eMLR estimate of Canthro. This study determines that the eMLR method is unable to describe Canthro uptake for a sampling interval of greater than 30 years if the error is to remain below 20% for many regions in the Southern Ocean, Atlantic Ocean, and western Pacific Ocean. These results suggest that, for many regions of the ocean basins, hydrographic field investigations have to be repeated at approximately decadal timescales in order to accurately predict the uptake of Canthro by the ocean if the eMLR method is used.