Methane hydrates are widely distributed along continental margins, representing a potential source of methane to the ocean and atmosphere, possibly influencing Earth’s climate. Yet, little is known about the response of methane hydrates to global climate change, especially at the timescale of glacial-interglacial cycles. Here we present a chronology of methane seepage from seep carbonates derived from a series of tens to hundreds of meters long hydrate-bearing sediment records from the South China Sea, drilled at water depths of 664−871 m. We find that six out of seven episodes of intense methane seepage during the last 440,000 years were related to hydrate dissociation, all coinciding with major interglacials, the so-called Marine Isotope Stages 1, 5e, 7c, 9c, and 11c. Using numerical modeling, we show that these events of methane hydrate instability were possibly triggered by the rapid warming of intermediate waters by ∼2.5−3.5 °C in the South China Sea. This finding provides direct evidence for the sensitivity of the deep marine methane hydrate reservoir to glacial-interglacial climatic and oceanographic cyclicity.