In campaign terms, these areas definitely have some human river traffic and some human settlements, but it is mainly dominated by water-based creatures and monsters. This is especially true in the main lakes that have formed along the way.
All the river tributaries to the Colorado come from the east, from the Arizona side. There is nothing to the California side of the river, just harsh dead desert, effectively cutting the region off from the Pacific coast.
Giants and their Fishing Holes
An adventuring tourist to any one of these river lakes is likely to find Mountain Giants frolicking in the cool water, or fishing for giant catfish and giant crayfish for their evening meal.... [For the sake of gaming adventure, I am treating the man-made lakes formed by dams as existing in the same places, but the dams are non-human in origin. Thus, the dams are either natural features, or the creation of Giants, or other giant creatures.]
Lake Powell in the north part of the state, and Lake Mead near Sin City are the major huge lakes on the river, with hundreds of miles of jagged coastline and dark depths housing all manner of dangerous beasts. Along the south-flowing stretch of the river are found a series of smaller bodies of water: Lake Mohave, Goose Lake, Lake Havasu, and the Imperial Lake.
Aside from giant varieties of fish, eels, frogs, spiders, snakes, and crustaceons, other water creatures to be found in the lakes include aquatic ogres, aquatic trolls, dragon turtles, eyes of the deep, nereids, water nagas, sea hags, froghemoths, and sea serpents.
Humans Along the River
The only humans to be found settled in such areas tend to be powerful recluses who have the wherewithall to survive in such hostile regions. Aside from the ever-present network of druids, I am thinking mainly of magic users, with the rare chaotic-minded psionic. Perhaps a retired ranger or an exiled fighter lord on the run from justice can be found holed up in some river canyon as well.
Rumors of their powerful magics and huge loot stash would definitely attract wandering treasure hunters and adventures. Surely the old wizard/dread lord is long dead by now, his lair just waiting to be found and treasure hauled away....
Crabmen of the Salton Sea
The great inland Salton Sea is fed by the runoff from a branch stream of the Colorado on its far southern leg near Yuma. [For fantasy campaign purposes, I will consider the All-American Canal that runs along the US-Mexico border to be a natural stream that feeds the Salton Sea.]
The Salton Sea is a swarming nest of Crabmen civilization. They like the semi-salty water of the isolated inland sea, rarely venturing upsteam into the fresh water river or downstream into the open-water depths. Their strength and numbers prevent any permanent human settlement in the area.
Human forays into the Salton Sea are occasionally conducted to obtain some of the magical artifacts of the Crabmen, which are said to provide their human possessors with great survival advantages in watery environments... The captains of the Colorado River merchant fleet are said to possess such items, but it is not known whether they were obtained by force or by trade.
Storkmen of the Baja Gulf Delta
The Colorado continues its final leg downstream to empty into the Baja Gulf in a shallow water delta. The streams of the delta are too shallow for anything but small boats, thus, no ocean going vessels can sail upstream. The area is largely wild and unpopulated by humans, but is a friendly home to all manner of animal and sea life.
Huge flocks of birds are especially prominent here, with some sort of avian civilization ruled by the intelligent Storkmen. For the most part, the Storkmen lords are unfriendly to human intrusion upon their lands. However, the Storkmen are known for their love of finely crafted jewelry and glimmering statues (which are apparently helpful in their mating rituals), which allows for a certain amount of mutual trade. Human merchants have been known to set up arrangements with the Storkmen allowing them passage to conduct their trading business with ocean going suppliers.