In J. R. R. Tolkien's fictional universe of Middle-earth, the Great Plague was a disastrous pestilence.

The Great Plague began in the east beyond Mordor, reaching Osgiliath in 1636 of the Third Age, just a year after King Minardil of Gondor had been killed at Pelargir by the Corsairs of Umbar, and only two centuries after the Kin-strife of Gondor. The new king, Telemnar was killed together with his kin, as well as many others of the Dúnedain. After the Kin-strife this further destroyed the people of Gondor.

The Plague had first hit Rhûn and Rhovanion, and after it had passed more than half the folk of the Kingdom of Rhovanion had been killed. From Osgiliath the plague spread west and then north. Enedwaith and Dunland were scarely affected, but the Plague regained strength as it went north, and Minhiriath (the southern part of Cardolan) was especially hit hard. The last of the Dúnedain of Cardolan died on the Barrowdowns, and evil spirits from Angmar and Rhudaur entered the realm.

Arthedain further to the north and the Shire were scarcely affected, although the Hobbits recorded casualties in the South Farthing. Arthedain still defended Fornost to the north.

The city of Osgiliath was especially hit hard, suffering the highest casualties outside of Rhovanion. Many fled the city and removed to Ithilien and Anórien, and Minas Anor became the King's seat.

The casualties were so high that the fortresses guarding Mordor were abandoned as the troops were recalled. For the next two centuries Gondor, as well as its enemies, did little but try and regain strength.