The Great Plague started in Rhovanion in the winter of 1635. From what is recorded, and Karen Wynn-Fonstad?’s Atlas of Middle-earth, it may seem as if it started in the East Bight on the eastern side of Greenwood, and that area was also worst affected in Middle-earth. The winter was cold and the horses and men of Rhovanion were driven into shelters, cramping their wooden houses and stables. Further away from the East Bight, the Plague caused fewer deaths in Rhovanion, but when it had passed, it was said that more than half of the folk of Rhovanion had perished, and of their horses also. Thus began the waning of the Northmen, for they were slow to recover.
Living nearby, the Easterlings also suffered. This may have saved Gondor for the time being, because from Rhovanion, the Plague spread southwest.
The Plague struck Gondor very hard, in particular Osgiliath where the mortality rate was as high as in central Rhovanion. Many fled from the city to the countryside and never returned, and the capital was moved to Minas Anor. The Plague spread so fast through Gondor and so many died that the troops that were stationed at remote camps and forts overlooking Mordor were recalled, leaving Gondor open to attack.
Calenardhon, never densely populated, was devastated and thereafter steadily denuded of inhabitants of Númenórean descent.
The number of deaths in Gondor could have been higher, but the skills in the arts of healing and medicine were still preserved from the wisdom of Númenor. This did not help King Telemnar, who died with all his children only a year after his father was slain at Pelargir by the Corsairs of Umbar. Telemnar was succeeded by his nephew, the son of Minastan, second son of Minardil: Tarondor. In Minas Anor, the White Tree died. And for almost two centuries, Gondor did little but try slowly to regain its strength.
The Plague continued to spread, both southwards, westwards and to the northwest. Dol Amroth was struck just as hard as the central parts of Gondor.
Luckily for Gondor, the Southrons seems to have been struck just as hard as the Easterlings.
Passing into Eriador, the Plague caused suffering among the Dunlendings. But as they dwelt apart and had few dealings with other men, they suffered less than most of the people of Gondor and Arnor.
Argeleb II was king when the plague came into Eriador from the South-east, and most of the people of Cardolan perished, especially in the southern portion of Cardolan, where Minhiriath was hard hit being almost entirely deserted, though a few secretive hunterfolk lived in the woods. All the remnant of the Dúnedain hidden among the Barrow-downs also died, and evil spirits out of Angmar and Rhudaur entered into the deserted mounds and dwelt there.
The Hobbits and all other peoples suffered greatly, but the plague lessened as it passed northwards, and farther north Arthedain was only marginally affected, so its people were able to continue defending Fornost.
Many parts of Eriador became desolate. In Enedwaith the remnants of the Dunlendings lived in the east, in the foothills of the Misty Mountains; and a fairly numerous but barbarous fisher-folk dwelt between the mouths of the Gwathló and the Angren (Isen).
The Plague started while the Shadow grew deep in Greenwood, and the fact that it began on the eastern borders of Greenwood may point to Sauron as the source of the Great Plague. And even if the enemies of Gondor suffered hard, the total effect of the Great Plague was in favour of Sauron. The descendants of Númenor were heavily depopulated, Osgiliath was almost emptied of people and Mordor was left open.