This has to be taken into scale with the remaining populations of the faction, so a quadrillion population losing billions doesn't exactly in the criteria just because of the number.  


***One Year War - Gundam*** 

True to its name, although One Year War took roughly about one year and escalated from the One Week War, the whole war took more than 55% of the humanity population thanks to the unrestricted warfare in the early part, where unrestricted nuclear weapon usage and colony drop attack was used without considerations.

One of the most devastating attack was when Island Iffish, a colony cylinder from Side 2, was redirected by the Principality of Zeon to drop at Jaburo, the Earth Federation's HQ in South America. However, due to the defensive attack, the colony split into parts and hit Australian city Sydney instead, annihilating countless millions of civilians and created 500km. crater that would later be known as the Sydney Crater. 

Despite the rather short timespan, it was one of the most devastating war in humanity history.

***Mass Effect***

I will just put it here because it's a well-known franchise.

The Reaper war started off as a blip on the radar of many races - An alien ship trying to breach into the Citadel Station - Sure, that looked quite hectic. No one gave much thought about it. 

The Citadel Council thought no one would buy the 'There are machine gods out there trying to kill us all' would be a nice public announcement, neither that people would believe it to begin with, so the preparation was stagnant at best against the further threat.

Two games later, the Reapers called the main invasion force and successfully entered Milky Way galaxy. The homeworld of the Batarian is in its path and was quickly annihilated - The Batarian Hegemony did not stand a chance, for they were even corrupted by the Reaper artifacts recovered from deepspace beforehand.

Humanity's bastion at Arcturus Station was quickly sidelined by the invading Reapers, who smashed the station and annihilated the central command along with the president before quickly proceeded to slip pass the Lunar defense line to establish beachhead invasion on Earth in all major capitals. While humanity was preparing for the defense, they already arrived and it was too late.

Countless civilians were slaughtered and turned into abominations to be used to attack Earth forces even further - Similar thing were happening across the galaxy, and not many planets could hold fast - Even the Turians, well-known for their military expertise, were grinded down by numbers during the course of war despite their bravery.

By the end of the war, few of each races remained and few in numbers - With Batarians converging on the near-extinction, if not for their rogue life distancing them from creating a unified society for the Hegemony was completely destroyed.

As for humanity - You get to decide how devastating the ending will be. It could be bad, but it could definitely be worse.

A completely annihilating war where massive casualties rack up incredibly quickly.