The Mount Mazama eruption (Crater Lake, USA) c. 7600 years ago counts among the largest eruptions of the Holocene, yet its impact on contemporaneous climate, environment, and humans remains incompletely understood. Here, we simulate the Mazama eruption using the Max Planck Institute Earth System Model with a volcanic stratospheric sulfur injection of 162 Tg S based on estimates from ice core records, to project potential impacts on global climate and society. The model simulations reveal severe and diverging surface climate anomalies in different regions of the world. We investigate specifically the regions of the Mediterranean and Near East, and southeast Asia distal from the eruption source, for which we project compounding extreme events. We argue that the compound occurrence of severe cooling and precipitation extremes likely had a significant impact on these main regions of human settlements and spread of agricultural practices, with crop failures due to drought, and potential flooding in areas experiencing extreme precipitation increase. Our study illustrates how very large volcanic eruptions can alter surface climate with varying and contrasting compound anomalies affecting much of the land surface. A volcanic event similar to the Mazama eruption may well occur in the next decades to centuries. Today, an eruption of this magnitude would pose substantial risks of multiple breadbasket failures, impacting food security globally, which in turn may lead to further societal upheaval. Studying very large past eruptions is imperative for better understanding the risks associated with low-likelihood, high-impact events – that global society is patently ill-prepared for.