The harmonica was originally owned by Celestia Denton and was inscribed with her name. After she was in a horrific car accident, the Nameless One kept her alive, altering the course of destiny. It appears that the Nameless One placed a spark of life essence within the harmonica, which was the source of Denton's continued existence.
Transformed into a mystical item of great power, the "Harmonica of Destiny" was next seen in the subways of Manhattan. It was being played by a young girl who turned out to be the mystical embodiment of Destiny. The girl fell in front of a subway train and when Doctor Strange attempted to rescue her, she told him that she was of no consequence, to save the harmonica. After making a split-decision, Strange decided to save the harmonica and later communicated with the essence of Destiny, who had exploded into a dazzling array of sparks after being hit by the train. Destiny informed Strange that all of those present at the subway station would have their destiny reshaped according to their actions. As Strange tried to save all those who were present, the Enchantress, disguised as the Valkyrie, went to his Sanctum Sanctorum and told Wong that Doctor Strange requested her to take it.
The Enchantress almost used the harmonica to destroy reality as we know it. The Thing managed to use the harmonica to restore reality and save the world. Later when the Thing and the Defenders were captured by the cult of the Nameless One, the harmonica was returned to Celestia. The leader of the cult, Van Nyborg, used the harmonica, his spells, and the life essences of both Doctor Strange and the Valkyrie to return the Nameless One to Earth. The Thing, thinking quickly, grabbed the harmonica from Celestia and destroyed it, disrupting the spell and releasing the life essence that kept Celestia alive. The Nameless One was lost back to his own dimension and Celestia's body turned into a pile of smoldering ash.