Nosgoth chronicles a previously-unexplored span of time in the events of Soul Reaver: the centuries between Raziel's execution and Raziel's resurrection, both events originally depicted in the introduction to Legacy of Kain: Soul Reaver.

Since the collapse of the Pillars and the holy war, Nosgoth's oppressed human population has carved out a harsh existence in slavery and exile, largely relegated to life as food in Blood farms. The land's emperor, Kain, and the Council – his six lieutenants – reign over the heartlands with their vampire clans. When Raziel, Kain's first-born lieutenant, betrays his master, Kain condemns him to execution in the Lake of the Dead. Before long, however, Kain himself disappears, abandoning the empire. Using the Chronoplast to travel through time, he departs in search of a means to restore health to the corrupt Pillars of Nosgoth, and the world itself.

Kain's surviving lieutenants remain to shepherd the decadent realm, but quickly succumb to mistrust, infighting, and, ultimately, civil war. Raziel's leaderless progeny, the Razielim, become victims to persecution from their brethren, and, now unrestrained by Kain's leadership, clan falls against clan. Nosgoth's humans capitalize on the escalating state of turmoil and distraction among the vampires to escape the blood farms, rekindling their own civilization.

Rebuilding cities and recovering skills over hundreds of years, the human slaves come to represent an increasingly credible threat to the vampire race. They form an army, and a devastating attack on their enemies' outposts begins. The clans settle their disputes and reunite in an uneasy alliance to quell the insurgency. The new war between both races for domination of Nosgoth ensues.