The effect of the El Niño/Southern Oscillation (ENSO) on tropical rainfall variations of the past 2 millennia is largely unknown. High-resolution monsoon records are sparse, despite the role of ENSO in generating global hydrologic anomalies in modern climate. To investigate the relationship between ENSO and the Central American Monsoon, we generated a high-resolution (∼2.9 years/sample) oxygen-isotope monsoon rainfall record from a U/Th-dated stalagmite (180 B.C. to 1310 A.D.) from the Isthmus of Panama. We present evidence for a weakened monsoon during the “High Medieval” (1100–1200 A.D.) and the Classic Maya Collapse (750–950 A.D.). Rainfall decreased and was more variable after 550 A.D., and the period 900–1310 A.D. was drier than the preceding millennium. A weaker monsoon corresponds with increased El Niño variability, and our data display statistical variance in the ENSO band. We conclude that ENSO variation has forced isthmian rainfall and may have contributed to hemispheric climatic anomalies at this time.