The incorporation of water isotopologues into the hydrology of general circulation models (GCMs) facilitates the comparison between modeled and measured proxy data in paleoclimate archives. However, the variability and drivers of measured and modeled water isotopologues, as well as the diversity of their representation in different models, are not well constrained. Improving our understanding of this variability in past and present climates will help to better constrain future climate change projections and decrease their range of uncertainty. Speleothems are a precisely datable terrestrial paleoclimate archives and provide well-preserved (semi-)continuous multivariate isotope time series in the lower latitudes and mid-latitudes and are therefore well suited to assess climate and isotope variability on decadal and longer timescales. However, the relationships of speleothem oxygen and carbon isotopes to climate variables are influenced by site-specific parameters, and their comparison to GCMs is not always straightforward. Here we compare speleothem oxygen and carbon isotopic signatures from the Speleothem Isotopes Synthesis and Analysis database version 2 (SISALv2) to the output of five different water-isotope-enabled GCMs (ECHAM5-wiso, GISSE2-R, iCESM, iHadCM3, and isoGSM) over the last millennium (850–1850 CE). We systematically evaluate differences and commonalities between the standardized model simulation outputs. The goal is to distinguish climatic drivers of variability for modeled isotopes and compare them to those of measured isotopes. We find strong regional differences in the oxygen isotope signatures between models that can partly be attributed to differences in modeled surface temperature. At low latitudes, precipitation amount is the dominant driver for stable water isotope variability; however, at cave locations the agreement between modeled temperature variability is higher than for precipitation variability. While modeled isotopic signatures at cave locations exhibited extreme events coinciding with changes in volcanic and solar forcing, such fingerprints are not apparent in the speleothem isotopes. This may be attributed to the lower temporal resolution of speleothem records compared to the events that are to be detected. Using spectral analysis, we can show that all models underestimate decadal and longer variability compared to speleothems (albeit to varying extents). We found that no model excels in all analyzed comparisons, although some perform better than the others in either mean or variability. Therefore, we advise a multi-model approach whenever comparing proxy data to modeled data. Considering karst and cave internal processes, e.g., through isotope-enabled karst models, may alter the variability in speleothem isotopes and play an important role in determining the most appropriate model. By exploring new ways of analyzing the relationship between the oxygen and carbon isotopes, their variability, and co-variability across timescales, we provide methods that may serve as a baseline for future studies with different models using, e.g., different isotopes, different climate archives, or different time periods.