The delta's first settlers were probably Nandor. Some of the Nandor who had lived upstream, in the Vales of Anduin under the Misty Mountains, passed to its Mouths southward. After they were gone, the "lesser men" settled there, though they were likely in conflict with Haradrim. After the coming of the Númenóreans, the confluence of cultures in the Ethir and Pelargir formed one of the earliest forms of Westron. The Númenoreans made a passage taken by the ships going to and from Pelargir.
During the Drowning of Númenor, the shores of the Bay of Belfalas had retreated a great distance, putting Pelargir much farther inland than it had been in its beginning. Afterwards, the Anduin carved a new path by many mouths to the Bay.
The delta was populated mostly by fishermen and other sea-crafty folk, and became an important part of Gondor in the days of Tarannon, the first Ship-king.
During the War of the Ring, some hundred fishermen that could be spared from the boats were sent to the defence of Minas Tirith. This left the Mouths themselves open to Umbarian conquest, but the occupation did not last very long; Aragorn and the Grey Company liberated it several days later.