107,445 BCE

In approximately 110,000 BCE, human colonists discover vessels containing fine organic powder on both inhabited and deserted worlds near the edges of the Milky Way Galaxy. This powder is administered to the domesticated Pheru, which begin to exhibit more docile behavior; unbeknownst to humanity and their San 'Shyuum allies, the powder begins to alter the Pheru's genetic makeup. Centuries later, the Pheru begin to show outward signs of mutation and cannibalize one another. Soon, both humans and San 'Shyuum who are exposed to the powder begin to exhibit the same symptoms.

The Flood then begins to take over hundreds of worlds, turning its victims into misshapen forms. Humanity begins all-out war against the Flood. Eventually, humanity discovers a way to fight the Flood and contains the infection while it is still relatively minor, removing all traces of its existence within the Milky Way Galaxy. Throughout the war, most Forerunners remain unaware of the Flood's existence, believing stories of the parasite to be an excuse for humanity's aggressive expansion. The Flood are not seen again for ten millenia.

During their war against the Flood, humanity desperately invades a minor sector of Forerunner space, sparking the Human-Forerunner war.