The Eastern Plaguelands is the more heavily devastated half of the Plaguelands, the remnants of the Kingdom of Lordaeron. They are located east of the Western Plaguelands, north of the Hinterlands, and south of the Ghostlands.

The Scourge's rule here is supreme. Their northern capital of Stratholme is here, under the command of the lich, Kel'Thuzad. The ground is brown, ugly, and sick, the trees corrupted into giant mushrooms and the air polluted with orange mist. Undead, necromancers, and Damned cultists prowl the land. The Scarlet Crusade boasts a large army and battles fervently and vainly against the Scourge; outsiders are also unwelcome. Amani forest trolls strike from the north, attempting to reclaim their ancestral empire.

The area is roamed by mutant creatures and soldiers of the Scourge, while members of the Scarlet Crusade fight a constant battle to drive the Scourge out of Stratholme from their Chapel and key base at Tyr's Hand. Only a small camp maintained by the Argent Dawn remains friendly to all, welcoming adventurers that would lend a strong arm or spell. Located at Light's Hope Chapel, this staging area serves as a last bastion of Light in a land blanketed in darkness.

In the opening hours of the Third War, the investigations into the origins of the Scourge led Prince Arthas and Jaina Proudmoore through the Tirisfal Glades and what is now the Western Plaguelands (more specifically, the towns of Andorhal and Hearthglen), where they confronted the necromancer Kel'Thuzad and his Cult of the Damned. Kel'Thuzad told Arthas to seek out the leader of the Scourge in Lordaeron, the Dreadlord Mal'Ganis, at Stratholme. While en route via Hearthglen, Arthas and Jaina were joined by Lord Uther, master of the Silver Hand. When they arrived at Stratholme, Arthas realized that the villagers had been infected with the Plague of Undeath. When Uther refused to obey Arthas' command to purge the city, Arthas relieved Uther of command and disbanded the Silver Hand, then slaughtered the townsfolk himself. After hunting down Mal'ganis in Northrend, Arthas returned as one of the Lich King's death knights and toppled the Kingdom of Lordaeron by murdering his own father, King Terenas. After the fall of Lordaeron's capital, the plague spread throughout the northern regions of Lordaeron, turning them into the blighted lands they are today.

The resistance against the Scourge was particularly bloody at Darrowshire, where the ghoul Horgus the Ravager and the death knight Marduk Blackpool (alias Marduk the Black) led an army of Scourge against the town. Only surviving paladins under Davil Crokford and the Darrowshire militia under Captain Joseph Redpath were able to stand in their way. Though they put up a valiant fight, the defenders of Darrowshire were not enough to stave off the endless legions of Scourge. Davil managed to defeat Horgus in combat, but he succumbed to the horrific wounds the ghoul had inflicted. Captain Redpath fell to Marduk's necromancy, his soul taken from his body and corrupted into the service of the Scourge, where he proceeded to turn on his fellows and tear Darrowshire apart, killing everyone who hid in their homes.

After the fall of Lordaeron, the Scarlet Crusade attempted to retake the shattered kingdom from both the Scourge and the undead renegades known as the Forsaken. In the Eastern Plaguelands, they took control of both the town of Tyr's Hand and the western districts of Stratholme, where they battle the forces of Baron Rivendare to gain control of the destroyed city. Eventually, the master of the Scourge in Lordaeron made his return to the blighted lands. From his citadel of Naxxramas, floating over the Plaguewood near Stratholme, he prepared to continue the work he began in the name of his master, the Lich King. Recently, Naxxramas floated away from the Plaguelands and reappeared over Dragonblight in Northrend, though it was replaced by Acherus: The Ebon Hold over the far eastern portion of the zone. From there, Arthas sent his death knights to exterminate both the Scarlet Crusade and the Argent Dawn and leave his grip over the Plaguelands unchallenged. But, there is that old saying about the best-laid plans of mice and men (and Lich Kings)...