Silicate weathering provides a stabilizing feedback in the global carbon cycle and has played a key role in keeping surface environments clement for the majority of Earth’s history. It was recently proposed that ophiolite emplacement at low latitude at ∼90 to 70 Ma and ∼50 to 40 Ma enhanced the rate of silicate weathering and led to global cooling that terminated the Early Eocene Climatic Optimum. In this study, we revisit this proposal with a series of models of varying complexities to investigate the likelihood that Earth’s climate was driven largely by ophiolite emplacement in the Paleogene. Our models are constrained by either marine Os isotopic records or the combination of carbon cycle, Sr and Os isotopic records, and solid Earth degassing rates. The proposed changes in ophiolite weathering are inconsistent with our Os isotope mass balance model. With our coupled carbon cycle and weathering proxy model, total global silicate weathering fluxes (including ophiolite weathering) slightly decreased or remained relatively constant from 52 to 42 Ma. This constancy in global silicate weathering fluxes is inconsistent with the idea that enhanced ophiolite weathering directly led to global climate cooling. However, our model results support the idea that the strength of the silicate weathering feedback (weatherability) has played a significant role in regulating the pCO2 levels through the Cenozoic. Further, the modeling toolkit developed here can be used to explore the role of mafic rock weathering in driving climate change in other intervals through Earth’s history.