The Middle Eocene Climatic Optimum (around 40 million years ago) was a roughly 400,000-year-long global warming phase associated with an increase in atmospheric CO₂ concentrations and deep-ocean acidification that interrupted the Eocene’s long-term cooling trend. The unusually long duration, compared with early Eocene global warming phases, is puzzling as temperature-dependent silicate weathering should have provided a negative feedback, drawing down CO₂ over this timescale. Here we investigate silicate weathering during this climate warming event by measuring lithium isotope ratios (reported as δ⁷Li), which are a tracer for silicate weathering processes, from a suite of open-ocean carbonate-rich sediments. We find a positive δ⁷Li excursion—the only one identified for a warming event so far —of ~3‰. Box model simulations support this signal to reflect a global shift from congruent weathering, with secondary mineral dissolution, to incongruent weathering, with secondary mineral formation. We surmise that, before the climatic optimum, there was considerable soil shielding of the continents. An increase in continental volcanism initiated the warming event, but it was sustained by an increase in clay formation, which sequestered carbonate-forming cations, short-circuiting the carbonate–silicate cycle. Clay mineral dynamics may play an important role in the carbon cycle for climatic events occurring over intermediate (i.e., 100,000 year) timeframes.