If you want a canon way of doing it, get the "Lords of Darkness" supplement, which details many different evil organizations in the realms.
Then have them all start suceeding at their various nefarious schemes.
The lost Netheril city of Shade (with their multiple epic level leaders) begins attacking the cities and kingdoms that border on the Anauroch desert. This ties up (or flat out kills) most of the epic level NPC's the region.
The Phaerim escape from their prison, and lead a horde of abberations out of the Anauroch, annihilating whichever kingdom they decide to make their home in.
The Zhentarim split between the Cyric worshipers of Darkhold and the Bane worshipers of the rest of Black Network. The Bane worshipers make an alliance with city of Shade, and aid them in their conquests. The Cyric worshipers begin guerilla warfare against everyone, and gain control of some powerful artifact that actually makes them a threat.
The Red Wizards also make an alliance with the City of Shade and the Zhentarim. This "Axis of Evil" initiates a Realms-wide war, with the Phaerim/Sharn conflict causing even more disruption.
The Cult of the Dragon converts a powerful dragon to their beliefs, and the newly created Dracolich Lord uses them to carve out a kingdom, with monster troops backed by high level necromancers and dracoliches. (Or have them come into power after the other factions have reduced the world to ashes, making their dark prophecy come true.)
While all this is going on, the Kir-Lanan discover or create the Ur-Priest class, and start an organized campaign to kill alll the clerics and worshipers of a specific deity, while making it look like internal struggles within the church are causing the problems. Eventually they weaken the god enough to kill it, and absorb it's power into an artifact. Using the artifact, they learn the location of the Tablets of Fate, and eventually they manage to steal them, which leads to a second Time of Troubles.
Naturally this causes even more massive disruption in the midst of the war started by the city of Shade and the Zhentarim. The Kir-Lanan begin hunting vulnerable deities with their newly acquired power, draining them into prepared artifacts. Eventually Ao steps in, and manages to stop them (probably with the aid of the PC's), but is mortally wounded in the process.
The Time of Troubles ends, but most of the gods are dead, and all the most powerful NPC's are dead. Almost all of the familiar kingdoms are in ashes, and the very geography has been altered by the war. The Cult of the Dragon is the strongest organization left...