Cynthia Lennon, 75, passed away in the presence of her family at her home in Spain.
A message on her son Julian Lennon's website said she died "following a short but brave battle with cancer".
It also said,"Her son Julian Lennon was at her bedside throughout. The family are thankful for your prayers."
Julian also tweeted a picture of hers, with the message "In Loving Memory" written above it.
Cynthia met John Lennon at art school in Liverpool in 1957 and the couple married just before Beatlemania transformed John into one of the most famous men in the world.
The couple divorced in 1968.