It could be an electro-mechanical-chemical-nuclear contraption. Exclude beings with super or paranormal abilities, and who are willing to wield those powers.
My candidate: The Hammer that Smashes Suns (yes, that’s its real name.) It’s some sort of a bomb hurled using a giant crossbow-like contraction, used by Osiris against his enemies in “Creatures of Light and Darkness.”
It’s cheating a little, but Cordwainer Smith’s ninety-million-mile long gold-colored spaceship was a very powerful weapon.
In the same story, Smith described a “chronopathic idiot,” a person who had a personal psionic power of jumping backwards slightly in time. That would be a pretty unanswerable weaponized power.
Time travel in general is a hellishly powerful weapon. Not only do I cause you to no longer exist…I cause you never to have existed at all. I don’t just kill you: I kill your entire time-line, affecting everything in your causally-linked cosmos. (And, who knows, it might affect everything in the entire cosmos.)
Didn’t Doc Smith’s Lensmen throw galaxies around? Anyway, they had pretty damn powerful weapons.
Creatures of Light and Darkness also had beingse who could travel forward and back in time (temporal fugue, an acquired skill) but I excluded those.
In Kurt Vonnegut’s Slaughterhouse-Five, the entire universe is accidentally destroyed when a Tralfamadorian pilot tested a new type of rocket fuel. Imagine the destruction it could cause if it were weaponized.
Starkiller Base. Blows up multiple planets for the price of one!
Hard to think of anything more powerful than Tengen Toppa Gurren Lagann, which is a mecha 10 Million Light Years big (*** 100 times the size of the Milky Way galaxy!!!***).
it is topped by the 52.8 billion light years tall *Super *Tengen Toppa Gurren Lagann in the movie (that’s 58% of the observable universe, kids!) but that’s much more of an energy being, not a sorta-mecha-sorta-energy construct like the smaller one.
Iain M Smiths Lazy Gun
Iain M Banks
the Zinder Nullifiers, from Jack Chalker’s The Return of Nathan Brazil. These essentially erase reality. They’re originally built to prevent beings named Dreel that “take over” bodies (a la The Thing in John W. Campbell’s story Who Goes There? and Carpenter’s adaptation of it, The Thing) from taking over galactic civilization, but then they lose control of it, and it threatens to destroy the universe.
I suspect that the Ultimate Nullifier (which Wolverine brought up) that The Watcher sends Johnny Storm after in Fantastic Four #50, but its use and power wasn’t discussed there, and I haven’t kept up with more recent comic book mythology on it.
Davros’s Reality Bomb from Doctor Who
The creator of the genocidal Daleks created a “bomb” that breaks the atomic bond of all matter, reality would simply “fall apart”
A bomb that destroys the universe…
Doh!
The Ultimate Weapon from Life, the Universe, and Everything connected the cores of all stars in the Universe together instantly, causing them all to go supernova – or at any rate it would have had it ever been deployed.
“Doc” Smith’s Lensman series from the 30’s-50’s have been mentioned, what with armored planets moving at multiples of lightspeed, negaspheres (planet-sized masses of ‘negative energy’ or anti-matter, and other goodies, but another series of his (The Skylark of Space) had a good one.
In effect, they could move SUNS from one place to another. The final battle was moving Billions of suns from one galaxy to another, placing them next to an existing sun so that they would explode (it’s the 1950’s folks, we were still learning), thus destroying the all-encompassing EVIL. Yep, destroy a galaxy by using another galaxy. It might not be the top, but you have to admit, it’s a good one.
In the uneven but frequently very good TV show Lexx the titular space ship is the most powerful weapon in the two universes. It is an organic based creation and feeds by destroying planets and eating the debris.
TCMF-2L
In a somewhat less fantastic vein, the one-ton iron spheres detached from a Bussard ramjet at .99 C and which impacted the planet Wunderland in one of the “Man-Kzin Wars” books were pretty damned devastating.
Well, we know it’s NOT the Death Star. 
If weaponized, it wouldn’t just just destroy it ALL, it would destroy MORE of it all!
Any weapon that destroys everything has to be the most powerful. But like infinity, they are all equally powerful.
So I’ll nominate The Great Gazoo’s doomsday weapon, which would have destroyed the universe with an explosive ZAM.
Don’t be too proud of this technological terror you’ve constructed. The ability to destroy a planet is insignificant next to the power of the Force.
Let’s be honest. This all a sci fi / fantasy wank off, so any opinion is just as meaningless than any other.
But I’m not impressed with weapons that are impressive JUST because they are absurdly big.
The ones that impress me as a sci fi wanker are the ones that are clever, or work in a way that would have not occurred to you, or ones that if the sci fi magic actually worked make you think “yeah, that would do it”.
A crappy example. You are fighting a very long lived race who breds very slowly. The enemy devises a virus that causes them to remember pretty much everything they experience. Pretty soon they are all driven crazy/overwhelmed/stopped in their tracks and the civilization comes to an end.