Think I would go with a large city that just died. There are enough real life events that could cause it, a quick illness like flu or ebola, or gas being released from a lake or volcano. In a fantasy game it could be a portal being opened to the wrong place, plane of ice, a gas world, or just the breath of evil god.
Dead would be the most common foe but would build up; zombie, skeleton, ghoul, lich. Then you would have your plants, shambling mounds, assassian vines and such, then small creatures move in, kobolds, carrion crawlers, banbits, orcs. Last it would be your adventures and cults.
The city would have to be know for something, trade route, mines, art, something and would just be over hill and dale from somewhere else (basicly it is not too far out of the way, just far enough).
Keeping it a ruin? That is a trick, I normally do cities as targets - you have the city as the center, the next ring is villas, noble homes, ranches, a couple of small farming towns, people could take a day trip to the city, patrolled weekly but safe, rural stuff mostly. The next ring larger farms, timber mills and logger towns, only trips to the city would be holiday and special events, borderlands to wilderness, patrols are seen maybe once a month. The out ring would be the only one left and it would become more wilderness, that ring would setup the warnings and have the fear of the event because family still talk about it.