The Jewel of Medina, the debut novel by journalist Sherry Jones, was due to hit shelves on 12 August.
Random House said it had been advised the book "might be offensive" to some Muslims, and "could incite acts of violence by a small, radical segment."
"We decided, after much deliberation, to postpone publication," it added.
The decision was taken "for the safety of the author, employees of Random House, booksellers and anyone else who would be involved in distribution and sale of the novel," said the company's deputy publisher Thomas Perry in a statement.
The novel traces the life of A'isha, who is often referred to as Muhammad's favourite wife, from her engagement at the age of six, until the prophet's death.
Jones said that she was shocked to learn in May, that publication would be postponed indefinitely.
Random House's decision only came to light this week after The Wall Street Journal published a column by Muslim writer and scholar Asra Nomani, saying she was "saddened" by the turn of events.
Nomani argued that the publisher was afraid reaction to the novel could equal the furore caused by Sir Salman Rushdie's Satanic Verses.
Published in 1988, the book was condemned by the Islamic world because of its perceived blasphemous depiction of the Prophet Muhammad.
Sir Salman was forced to live in hiding for the next decade after Iran's then-spiritual leader, Ayatollah Khomeini, issued a fatwa ordering his execution.
In her article, Nomani said university professor Denise Spellberg, who had been sent a review copy of Jewel of Medina, had been instrumental in stirring up opposition to the novel.
Professor Spellberg, from the University of Texas in Austin, was quoted saying the book was "ugly", "stupid" and "soft core pornography".
Three days later, Professor Spellberg argued in the same newspaper that she could not have "single-handedly stopped the book's publication".
But she conceded: "I felt it was my duty to warn the press of the novel's potential to provoke anger among some Muslims."
Jones has never visited the Middle East, but spent several years studying Arab history and said the novel was a synthesis of all she had learned.
"They did have a great love story," Jones said of Muhammad and A'isha.
The author, who has just completed a sequel examining her heroine's later life, is free to sell her book to other publishers, Random House said.