[8][9] The region of the river in northern Nevada was sparsely inhabited by Numic-speaking people at the time of the arrival of European American settlers.

The first recorded sighting of the river was on November 9, 1828, by Peter Skene Ogden of the Hudson's Bay Company, during his fifth expedition to the Snake Country.

Ogden explored the river for several hundred miles, blazing a trail along it and making the first known map of the region.

Washington Irving's 1837 book describing the Bonneville expedition called it "Ogden's River", the name used by many early travelers.

The river provided drinkable water to earlier travelers on foot, but later emigrants using wagons required the significant riparian vegetation along its length as forage for their draft animals.

The middle basin has a drainage area of about 7,800 square miles (20,000 km2) and lies between Palisade and Emigrant Canyons, a narrow gap located just downstream from Comus.

The lower basin is an area encompassing some 4,100 square miles (11,000 km2) from below Emigrant Canyon and extending through the Humboldt Sink in northwestern Nevada.

At Battle Mountain, the river turns northwest for approximately 50 miles (80 km), then west at Red House and past Golconda and a spur of the Sonoma Range.

Stream-gauge measurements undertaken by the United States Geological Survey suggest that Palisade Canyon, between Carlin and Beowawe, is the point where the river's flow ceases to increase and begins to decrease.

Also, since the Humboldt's water comes almost exclusively from snowmelt, its flow is highly variable from season to season (peak flow occurs during the spring melt) and from year to year (depending on the amount of snow every winter)[2][15] The Lahontan cutthroat trout (Oncorhynchus clarki henshawi) is an inland subspecies of cutthroat trout endemic to northern Nevada, eastern California, and southern Oregon.

[21] North American beavers (Castor canadensis) seem to have been making a comeback in Elko County, possibly due to less fur trapping combined with reduced consumption of riparian willow and other vegetation by cattle.

Maggie and Susie Creeks, which enter the Humboldt River near Carlin, have benefited from 20 years of work by ranchers, agencies, mines, and non-profit groups via improvements in grazing techniques and specific projects.

Newmont's shallow groundwater monitoring wells along Maggie Creek have shown about a 2-foot (0.6 m) rise over the past 17 years[which?]

Stream flows are more perennial, making more water available for wildlife and livestock and protecting populations of native trout.

[23][24][25] The Humboldt River and its surrounding areas have raised some concern about the increasing levels of toxic elements such as arsenic and mercury.

[27] Whether it was leaching from the gold mining process or leftover mercury ore, these toxic elements entered the environment and waterway.