The "hopeless holy war", and "the taming of the humans", as Raziel variously described it, was mentioned in the backstory of Legacy of Kain: Soul Reaver. An unseen event in Nosgoth's history, this war followed soon after the raising of the lieutenants in the post-Blood Omen era, and represented the beginning of the Soul Reaver era. The conflict lasted less than a hundred years.
The major human kingdoms stood against the rise of Kain's empire, but the lieutenants of the Council continued to build their clans by recruiting human victims. As the empire grew, the vampires decimated their enemies and conquered Nosgoth. Though some scattered resistance was tolerated after the war's end to challenge fledglings, humanity was thoroughly domesticated.
Once Kain organized the Lieutenants, the early part would have been more about subterfuge, and corrupting/destroying large cities. (If you have seen Avatar: the Last Airbender.. it's sort of like how they took Ba Sing Se)
Later, once Kain's army rose as a credible military threat, the Humans would have started organizing or trying to organize into military Citadels. Epic battles would have ensued with the dead simply adding to Kain's army (using the flayed souls of his Lieutenants)
Assassination, Spec Ops, wet works, strategic military operations, and in some cases brute force would have been key to decimating human resistance. It would have been a great era to visit in another Kain game at the very least."
The raising of the lieutenants
|Nosgoth's historical events|
The holy war
Soul Reaver era