In terms of most people killed. (This is assuming there has been no situation where aliens came here, clobbered humanity, fade to black. Has there ever been a case of aliens winning?)
I think the aliens of Independence Day got in pretty good with their plan of attacking all major cities. I estimate death in the half billion range.
Runners up: The Wraith of Stargate: Atlantis. They’ve been munching on humans all over their galaxy for who knows how long, and they’re evolved to specifically feed on humans - good motivation for 1st place. Hard to say numbers, I’d guess according to the SG series, maybe a few million?
The Vogons in Hitchhiker’s Guide – just about everyone on Earth.
The aliens in “War of the Worlds,” all versions, kicked a lot of ass and took a lot of names and were scary besides, and we were only saved by them getting sick.
The aliens in Harry Turtledove’s Colonization series were pretty tough. They didn’t win, but came to a draw, as I remember.
Yep. When the entire earth is destroyed, all it’s assets, all it’s people (except one), and all it’s species of animals, what kind of hit would be harder?
Nitpick: two people survived from Earth, Arthur Dent and Tricia McMillan (also known as Trillian).
As stated upthread, the Vogons, making way for the Hyperspace Bypass
the Drej from Titan AE, destroying Earth and hunting down remaining Humans
the Daleks and Davros from NuWho, had the Reality Bomb not been altered by The Doctor, they would have been the top baddies, as the Reality Bomb would have destroyed reality itself (aside from the Crucible)
The Minbari. Had they not discovered what they discovered, they would likely have wiped out humanity.
There were very few human survivors of the destruction of Earth in Greg Bear’s (was it Eon?). More survivors than in HHGTTG tho. Plus we got our own back!.
Yes, but only one got away at the time of the explosion. Trillian had already been offplanet for months.
Later they were joined by Random Frequent Flyer Dent.
Yeah, but if you’re looking for sheer numbers killed, it may be better to look at books set in the far future, where humans have had a chance to…err…go forth and multiply more.
You people need to read and watch more science fiction. You’d think that Hitchhiker’s Guide was the only place the entire Earth got destroyed.
What about Titan AE, or the forthcoming The Battle or Terra?
Or Dan Simmons’ series Hyperion/The Fall of Hyperion/Endymion/The Rise of Endymion?
Or any number of “Last Man on Earth” stories (See the collection The Last Man on Earth
Of course, sometimes we do it to ourselves, as in any number of 1950s Nuclear Armageddon stories, or in ones like Alfred Bester’s “Adam but no Eve” – that one gets everybody
Right, which is why my vote would be for the Berserkers, from a series of stories by Fred Saberhagen (and several guest writers). A “race” of self-replicating starships, their sole purpose for existance is to eradicate intelligent life from the galaxy. Over the course of centuries they killed off countless alien races and billions of humans. Truly badass.
Not all the animals. The dolphins left in time.
Photino Birds.
They’re destroying the entire Universe (as we know it) to make it more comfortable for them. The XeeLee are trying to stop them. Both sides are making it uncomfortable for beings like humans. “Uncomfortable” as in “ant nest on a construction site.”
To be fair, in the last Hitchhiker’s book, the Vogons team up with Guide Mark Two and annihilate ‘an infinite multiplicity of planets Earth’, along with the survivors from the first attack. (Unless you believe the happy ending that Dirk Maggs tacked onto the radio show 
)
Galactus, Eater of Worlds.
The Straumli Perversion in Vernor Vinge’s A Fire Upon the Deep has to rank up there – destroying a large sector of the Galaxy with all the races living in it, has to outclass puny planet destroyers by several orders of magnitude.
The Tyranid race from Warhammer 40.000 is pretty hard hitting. When one of their hives encounters a human world (well, any world really, but we’re focusing on humans here) , the end result is a planet scrubbed down to the bedrock. Every plant, animal, even the topsoil and the atmosphere are meticulously devoured (in the space of a few days IIRC). Think galactic army ants.
Considering even the humongous hive fleets encountered by mankind so far are likely to be mere scouts for the real invasion, it’s a good bet they’ll eventually gobble up the whole Universe, assuming the Necrons don’t destroy Life itself first, or the forces of Chaos warp reality into everlasting Hell first, or… you get the drift.
Then there’s the case of Haruhi Suzumiya, who looks like a Japanese high-school girl, but who apparently destroyed and re-created reality three years ago. As a result she needs to be watched constantly by agents from three different extraterrestrial agencies, to make sure she doesn’t destroy reality again.