Various trails and wagon roads leading to the Cariboo goldfields lay across the low-hill range north of Quesnel Forks in the basin of the Cottonwood River.

The river took its name from Jules-Maurice Quesnel, who explored this region with Simon Fraser in 1808.

The Quesnel River supports a number of fish species, the most significant of which are Sockeye salmon (Oncorhynchus nerka), Rainbow trout (Oncorhynchus mykiss), Largescale sucker (Catostomus macrocheilus), Longnose sucker (Catostomus catostomus), Redside shiner (Richardsonius balteatus), Northern pikeminnow (Ptychocheilus oregonensis), Peamouth chub (Mylocheilus caurinus), and Lake chub (Couesius plumbeus).

[6] The salmon run of sockeye salmon experienced a major recovery in the late 20th century, sometimes surpassing the Adams River as the greatest sockeye producer in the Fraser basin.

[6] However, the river, wildlife, and nearby water sources is threatened by 10 million cubic meters of contaminated mine waste that escaped in August 2014.