Spheres of Annihilation. Or Umbral Blots ('living' Spheres of Annihilation!). A deity of entropy or destruction is slain by some epic adventurers, or by enemy/rival deities, only for them to find that, with the living manifestation of Entropy and Destruction now, well, destroyed, the raw essence of these forces is released and no longer constrained by physical form and deific will. The dead deity forms into swarm of Umbral Blots that rapidly spread all over and obliterate everything.
Perhaps a few scraps of the world will survive by the grace of whatever deities escape to other multiverses with chunks of their godly realms and perhaps some of their servants and worshippers. Perhaps not, since the Umbral Blots might not be inherantly sensed by the deities (in Deities & Demigods, a deity can sense big events related to their portfolio; but with the god of destruction/entropy dead, would there be anyone left who could sense the event due to their portfolio?). A deity noticing one or a few Umbral Blots in an area won't necessarily think anything's wrong; some lich or evil deity is bound to create the buggers once in a while, whether purposeful or through a botched epic-ish experiment; so they might just send some minions to attempt destroying the few Umbral Blots they noticed, but then they might be in trouble if some of the other Blots enter their godly realm.
Alternatively: the Far Realm invades. Some crazed, epic wizard/alienist has discovered a terrible secret deep in the Far Realm, and returned to the material plane to begin using that secret to open rifts to the Far Realm all over the place; Plane Shift to each plane, open a few rifts in various places there, then move on to another. The rapid opening of Far Realm entry points across the multiverse attracts the attention of Far Realm monstrosities that predate the gods or something..... The Far Realm begins invading in earnest, and all the world's alienists work to quicken the expansion of each rift, bringing in gads and gads of squamous horrors whose very appearance is enough to drive mortals insane, whose very entry into the material plane is a horrible and perverse violation of nature, sending the natural elements and forces of the material plane into riotous, violent turmoil. Fey, elementals, animals, vermin, plants, and more begin attacking everything around them, driven mad by nature being virtually r@ped by the Far Realm's wretched essence.
Perhaps the Far Realm is the multiverse as it existed before time, before the gods had taken form and reworked everything to their Will, making an orderly and rational multiverse to inhabit and manipulate. But since the Far Realm existed before time, it could not truly be undone. And eventually, its impossible physics created an anomylous pattern that broke the division of time and space that lay between reality-as-the-gods-made-it and the primordial Far Realm. The Far Realm becomes like anti-matter, for its very essence and matter was used to create the reality as mortals know it, and when the Far Realm begins to coexist with the multiverse, its impossible dual existence annihilates the portions of reality that were made from it. Or something.
