Relatively little is known about the relationship between the Indian summer monsoon (ISM) and the El Niño-Southern Oscillation (ENSO) on the centennial timescale during the Holocene. We present a well-dated high-resolution X-ray fluorescence (XRF) scanning record from a sediment core from Lake Qionghai on the southeastern Tibetan Plateau, which reveals the impact of ENSO activity on ISM variability. The results indicate a gradual drying of the regional climate on the sub-orbital timescale, which is in broad agreement with ISM changes controlled by Northern Hemisphere summer insolation. Additionally, centennial-scale drought events occurred at around 6230–5740, 4620–4250, 3820–3540, 3210–2440, 2180–1320, and 1000–615 cal yr B.P. and are consistent with enhanced ENSO activity, documenting the occurrence of ENSO-related drought events in the Holocene. Both ISM oscillations and ENSO variability show significant 350-yr, 500-yr, and 800-yr cyclicities, and there is a highly significant negative relationship between the ISM and ENSO at these cyclicities, indicating that a weak ISM was related to increased ENSO intensity, and vice versa. Our findings provide evidence for the modulation of ISM intensity by ENSO variability on the centennial timescale during the Holocene.