In the 13th century, Ayesha found herself incarnated in China, lacking a powerbase. To mend this, she contrived to kill and replace the goddess Hsi Wang Mu, or the Royal Mother of the West, as she was known. After killing the goddess, Ayesha became the new ruler of Hes, or Fire Mountain, previously known as Mount K'un Lun.
In 1872, she met Allan Quatermain.
She has been waiting for 2000 years for the reincarnation of her lover Kallikrates, whom she had slain in a fit of jealous rage until she believed that one of two travelers who find her, Leo, is his reincarnation.
Ayesha takes the two men to see the pillar of fire, wanting Leo to bathe in it as she did so that he can become immortal and remain with her forever. His doubts about its safety lead her to step into the flames once more. However, with this second immersion she reverts to her true age and immediately withers and dies. Before dying she tells Vincey, "I die not. I shall come again." Eventually they found her again.
An effigy of her by her cult was adorned in the British Museum.
In Nemo: The Roses of Berlin, Ayesha forms an alliance with Adenoid Hynkel as part of the latter's plans to conquer Africa. As a condition of their alliance, Ayesha has Hynkel kidnap Janni's daughter Hira Dakkar and her husband Armand Robur as part of a plan to lure Janni and her husband Broad Arrow Jack into a trap. However, in a confrontation in the Berlin Metropolis, Ayesha is beheaded by Janni after a furious sword fight.
In 1975, Janni Nemo uncovered a German-Tomanian project in South America that involved many Ayesha clones, along with clones of Adenoid Hynkel as well. Nemo's crew killed all of the clones.
In the opening pages of Century: 2009, Ayesha is mentioned by Colonel Cuckoo as he shares a drink with Orlando, in Q'mar, as an example of a fellow immortal who lost their mind to bloodshed and brutality.