According to legend, Agamotto emerged from the tear of Oshtur, benevolent Elder Goddess of Earth, as she was moved by the unyielding joy of a blind boy, circa 25,000 BC, though it is now known that Agamotto was already an adult and the Sorcerer Supreme during the Stone Age, in 1,000,000 BC. He was born a mortal (but not a human).
He was initially tutored by Oshtur, and his subsequent journey to discover the secrets of magic and find Oshtur led to the formation of the paths of magic power. Agamotto also served as Earth's first Sorcerer Supreme, defending it and its reality against such threats as Dormammu[ and the Fallen alongside other powerful beings assembled as the Stone Age Avengers.
Agamotto created a number of magical artifacts. The Eye of Agamotto and the Orb of Agamotto were used by Doctor Strange. Agamotto is also credited with the creation of the Book of the Vishanti.
The fourth Ring of Raggadorr was freed from the Dungeons of Dyzakk by Agamotto during his travels throughout the dimensions.
At some point, he became one of the few mortals sorcerers, such as Watoomb, to become a principality, a higher being invoked for power.
Agamotto and the Vishanti were worshiped at the Temple of the Three. His avatar was Cadaver, the Pale Horseman. Doctor Druid was forced to unmake Agamotto's Moebius Stone, but not before it transformed Cody Fleisch into Cadaver, Agamotto's agent.
During the War of the Seven Spheres, the Vishanti battled their rivals, the Trinity of Ashes. Despite an initial refusal, Doctor Strange was enlisted to serve them in the war. After their victory, he was returned to Earth.
Agamotto's appearance varied when he was encountered in his realm. He was known to appear to Doctor Strange as a caterpillar smoking a pipe in a realm that appeared to be out of Alice in Wonderland, capable of human speech and was not intimidated by Galactus. He is actually the entire dimension itself, as was why Galactus was unable to destroy him permanently. During a quarrel with Galactus, he assumed a more menacing version of the same form.
When Silver Dagger was placed into the dimension, Agamotto tried to convince him to stay. Silver Dagger eventually escaped. This was later revealed to be a ploy by Agamotto to see if Silver could change when in possession of an old version of the Eye Of Agamotto.
Agamotto was behind the demonic invasion of earth as he saw the previous Sorcerer Supreme, Dr. Strange, as a failure and the current one, Jericho Drumm, as inexperienced. He first appeared to Iron Fist after possessing him and dragging him to the spirit realm. Using the guise of the Ancient One, he convinced Rand that Dr. Strange had stolen the Eye of Agomotto and was unworthy of it. After a brief fight, Iron Fist realized he has been tricked. Agamotto then appeared as a tiger, but he changed back into his true form, then possessing the New Avengers to attack Strange. Doctor Voodoo arrived and freed the New Avengers and eventually sacrificed his life to kill Agamotto by destroying the eye and orb of Agamotto.
Despite his death, however, Agamotto still has a mystical connection to Iron Fist, whom he previously trapped in his dimension when his power possessed Iron Fist in interfering with the Immortal Weapons mission in closing the gate to the Eighth City until War Machine knocked Iron Fist out. Gwenpool claimed Agamotto gave her her magic rocket launcher.
Eventually, Agamotto returned to life through unknown means and later reappeared with Oshtur to talk to Drumm about Hoggoth’s situation.