The human history of the Dead Sea goes all the way back to remote antiquity. Just north of the Dead Sea is Jericho, the oldest continually occupied town in the world. Somewhere, perhaps on the Dead Sea's southeast shore, are the cities mentioned in the Book of Genesis which were destroyed in the times of Abraham: Sodom and Gomorra and the three other "Cities of the Plain" - Admah, Zeboim and Zoar (Deuteronomy 29:23). King David hid from Saul at Ein Gedi nearby.

The Greeks knew the Dead Sea as "Lake Asphaltites", due to the naturally surfacing asphalt. Aristotle wrote about the remarkable waters. During the Egyptian conquest it is said that Queen Cleopatra obtained exclusive rights to build cosmetic and pharmaceutical factories in the area. Later, the Nabateans discovered the value of bitumen extracted from the Dead Sea needed by the Egyptians for embalming their mummies.

Prominent personages linked with the Dead Sea and its surroundings are Herod the Great, Jesus of Nazareth, and John the Baptist. Also in Roman times some Essenes had settled on the Dead Sea's western shore; Pliny the Elder identifies their location with the words, "on the west side of the Dead Sea, away from the coast ... [above] the town of Engeda" (Natural History, Bk 5.73); and it is therefore a hugely popular though not uncontested hypothesis today, that same Essenes are identical with the settlers at Qumran and that "the Dead Sea Scrolls" discovered during the 20th century in the nearby caves had been their own library.

King Herod the Great built/re-built several fortresses and palaces on the Western Bank of the Dead Sea. The most famous was Masada, where, in 66-70 AD, a small group of rebellious Jewish zealots held out against the might of the Roman Legion, and Machaerus where, it has been argued from the Gospel according to Luke 3:20, that John the Baptist had been imprisoned by Herod Antipas and met his death.

The remoteness of the region attracted Greek Orthodox monks since the Byzantine era. Their monasteries such as Saint George in Wadi Kelt and Mar Saba in the Judean Desert are places of pilgrimage.

In Islamic tradition, the Dead Sea was about the land in which the Prophet Lut (Lot in the Hebrew scriptures) lived. His tribe had done wrong (act of homosexuality) and had therefore been given a punishment for such deeds. The punishment arrived when angels were sent down by Allah to Lut. The angels raised the land where the prophet's tribe lived and threw it back into the ground, causing the ground near the impact to cave in. Thus, the lowest land on Earth was formed because of this punishment. The sinners were destroyed and the followers were saved. According to some interpretation, the sura of ar-Rum of the Quran refers to the Dead Sea as the lowest place on earth.

Bedouin tribes have continuously lived in this area, and more recently explorers and scientists arrived to analyze the minerals and conduct research into the unique climate. Tourism in the region has been developed since the 1960s.

The world's lowest road, Route 90 (Israel), runs along the Israeli and Palestinian (West Bank) shores of the Dead Sea at 393 m below sea level.