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Currently, I have two examples in my mind:
Halo (Halo video game series; 2001): Can destroy all sentient life within three galactic radii
The Moment/ Eye of Discord/ Galaxy Eater (Doctor Who (2005) TV series; 2013): Can destroy entire galaxy within a moment
What sci-fi work first showed a weapon of galactic-scale mass destruction?
1930: "The Triple Ray", a short story by R. V. Happel in Amazing Stories Quarterly, Fall 1930, available at the Internet Archive.
Plot summary by Everett F. Bleiler in Science-Fiction: The Gernsback Years:
Professor Lucius Raymond is the inventor [of] two rays, the Twin Ray and the Triple Ray. The famed Twin Ray, a combination of ultraviolet and infrared, amounts to a disintegrator. Its source is an adapted Crookes' tube, with an unmentioned radioactive substance. A demonstration of this ray to the Germans leads to their retreat from Paris. (While the author is not clear, this seems to refer to a second world war.) This ray, in addition to being the prize weapon in the American arsenal, has extensive peaceful uses.
The Triple Ray, which destroys atoms, has been discovered almost by accident. On the single occasion that it is used, it drills a hole through a hill. More, it continues on and slices the top off a nearby mountain. Then it leaves the solar system and disrupts several stars. And it continues, moving faster than light. Since the universe is finite and space is curved, the ray will continue on around the universe, spreading, and return to disintegrate Earth. It will eventually devour the whole universe.
Excerpt from the story:
My curiosity vastly aroused by his letter, I took the first opportunity to see my old friend and learn what discovery had so upset him. Of the truth of his contentions I will say nothing other than that in so far as I was able to follow him in his deductions and experiments every fact seems to bear out his theory. His first discovery at the observatory was that the tremendous energy released from the mountain lodge, while he was attempting to measure the speed of the Triple Ray, had formed into an interstellar ocean of destruction, rushing madly through outer space, engulfing all matter it encountered and converting it into its own destructive nature.
It was, indeed, in the very same lodge only a few days before his death that Lucius, flat on his back from two strokes which left him paralyzed below the waist, slowly and carefully explained to me fully for the first time the exact nature of his discoveries at Dudley. I will give this in his own words, since it is thus that I best remember what he said to me.
[. . . .]
"It is for this reason that I cannot say how far in space the thing has traveled nor where it may be now. But this I do know and have proven many times over. The ray is traveling, not in a straight line after all, but instead in a closed circle, and must by every law of mathematics return again to its beginning. And since I have been able to learn by experiment that it renews and increases itself by that which it destroys, I have no particle of doubt in my mind but that on its return to the earth our planet will be utterly annihilated.
"The circle is vast, I know, for it was months after I first began to trace its course on an astronomical map that I was able to detect the slight deviation of the arc. It must travel the very fringes of the known stellar spaces where it takes light a thousand million years but to cross. Yet so terrific is the ray's speed that it may carry it round and back, I fear, in a lifetime; perhaps less. And no sight of its return will give warning, since it precedes its own light as lightning seems to precede thunder. It is, in short, a natural force which will surely ride the universe until all active matter has come within its circle, as it must sometime, and been destroyed. And even then it will circle on until all time has ceased to be. Perhaps it will finally be the birth itself of a new and different universe. I do not know.
Sounds like space opera to me! E. E. "Doc" Smith's Skylark DuQuesne, 1965:
Dorothy’s face began to pale. “By that analogy you mean destroy the whole galaxy! How can such a thing be possible? It can’t possibly be possible!”
He told her how the operation could be performed. That apparatus that the Barlo women had dredged up out of nowhere had a lot of capabilities that did not appear on the surface. Blackie DuQuesne had perceived one set of those possibilities, and he and Blackie had been working on the hardware. They were calling it Project Rho.
The effects of Project Rho were to destroy two galaxies. One galaxy was destroyed by removing most of its stars:
In Galaxy A, where billions of suns had gone through the stellar cycle of evolution for billions of years, there was scarcely a corporal’s guard of primaries left. It was a strange, almost a frightening sight. For with the loss of the suns the composition of the galaxy had changed to something never before seen in all the plenum of universes. Nearly every sun had had planets; nearly every planet remained behind when its sun was stolen. Now they roamed at random—uncontrolled, barren, uninhabited—lacking not only the light and heat of their primaries, but freed from their gravitational reins as well.
The stars from galaxy A were teleported to the galaxy of the Chlorans, which in turn caused all its stars to explode:
Thus millions upon millions of Chloran planets were destroyed without any intelligent entity either giving or receiving warning that an attack was being made....
They died in uncounted trillions. The greeny-yellow soup that served them for air boiled away. Their halogenous flesh was charred, baked and desiccated in the split-second of the passing of the wave front from each exploding double star, moments before their planets themselves began to seethe and boil. Many died unaware. Most died fighting. Some died in terrible, frantic efforts to escape...
But they all died.
In the Star Trek episode "The Alternative Factor", 30 March 1967, A highly unscientific threat to destroy our entire universe plus an alternate one was revealed, destruction on a scale that makes mere galaxy-wide destruction seem infinitesimal:
KIRK: What's going on? This leaping from universe to universe. This wild talk about a murdering creature who destroys civilisations What's the purpose?
SPOCK: Jim, madness has no purpose or reason, but it may have a goal. He must be stopped, held. Destroyed if necessary.
KIRK: I don't follow you.
SPOCK: Two parallel universes project this. One positive, the other negative. Or, more specifically, one matter, the other antimatter.
KIRK: Do you know what you're saying? Matter and antimatter have a tendency to cancel each other out. violently.
SPOCK: Precisely. Under certain conditions, when two identical particles of matter and antimatter meet.
KIRK: Like Lazarus. Identical. Like both Lazarus', only one is matter and the other antimatter. If they meet.
SPOCK: Annihilation, Jim. Total, complete, absolute annihilation.
KIRK: Of everything that exists, everywhere.
And when Kirk meets the sane Lazarus:
KIRK: Antimatter?
LAZARUS: Here, yes.
KIRK: And if identical particles meet
LAZARUS: The end of everything. Civilisation, existence, all gone. I tried to stop him, Captain. That's why I took your dilithium crystals.
Of course "The Alternative Factor" was aired in 1967, after Skylark DuQuesne (1965) and The Star Kings (1947) were published.
Possibility might be a weapon in Edmond Hamilton's novel "The Star Kings." This weapon was the "Disruptor," able to annhiliate vast regions of space itself and hence all matter within it.
A somewhat different kind of galactic-scale destruction occurs in "M33 in Andromeda"* (1943) by A. E. van Vogt, which later became the climactic encounter of the fix-up The Voyage of the Space Beagle.
The relevant part of the Wikipedia plot summary:
In the last section, Anabis, a galaxy-spanning consciousness, is encountered. Once again, it is both malevolent, starving and aggressive, and under all circumstances must be prevented from following the ship back to any other galaxy. Anabis, which is essentially a galaxy-size will-o'-the-wisp, feeds off the death of living organisms, and has destroyed all intelligent life in its galaxy. It transforms all planets it can find into jungle planets through terraforming, since it is these kind of worlds that produce most life.
*The Andromeda galaxy is actually M31. M33, the Triangulum Galaxy, is the third-largest galaxy in the local group, after Andromeda and Milky Way.
=>There is a "curse" that could destroy the entire fictional civilization in a book called "The Magician's Nephew"(1955) by C.S. Lewis.
The Deplorable Word, as used in The Magician's Nephew, by author C. S. Lewis is a magical curse which ends all life in the fictional world of Charn except that of the one who speaks it.
=>There was also this 'The Illudium PU-36 Explosive Space Modulator' in the classic Bugs Bunny short Haredevil Hare in 1948. Marvin the Martian wanted to use it to blow up Earth because, as he said, "It obstructs my view of Venus". The explosive was in the form of a small red stick that resembled Dynamite that was screwed into a large telescope-like machine.
=>In E. E. Smith's The Skylark of Space series(written between 1915-1921) various planet-killers are used or discussed. Throwing planets and moons out of orbit, incredibly high-yield atomic or copper bombs, near-instantaneous dematerialization of physical objects and the teleporting of close to fifty billion stars in order to wipe out a Galaxy-wide alien civilization are all used.
