The QPR defender, 36, released a statement saying his "wonderful wife and soul mate" Rebecca Ellison had "passed away peacefully" at a London hospital.
Ms Ellison, 34, who married Ferdinand in 2009, had breast cancer.
She leaves behind three children, Lorenz, nine, Tate, six, and four-year-old Tia.
In a statement, Ferdinand said she died on Friday night.
"Rebecca, my wonderful wife, passed away peacefully after a short battle with cancer at the Royal Marsden Hospital in London," the footballer said on QPR's website.
"She was a fantastic loving mother to our three beautiful children. She will be missed as a wife, sister, aunt, daughter and granddaughter. She will live on in our memory, as a guide and inspiration.
"Myself, my parents Janice and Julian, along with Rebecca's parents Lesley and Stephen, would like to thank our families, friends and my club colleagues who have rallied around in these desperate days, weeks and months."
Ferdinand thanked the staff who treated his wife at the south London hospital, adding: "I would also like to express my gratitude for the dedication and expertise of the staff led by Professors Johnstone and Clark at the Royal Marsden.
"Their valiant efforts to prolong Rebecca's all-too-short life will not be forgotten."
Messages of support have been posted on Twitter from the world of football.
Former Manchester United goalkeeper Peter Schmeichel wrote: "Really sad news that Rebecca Ellison, the wife of Rio Ferdinand has passed away. My condolences to Rio, their children and the family. RIP"
BBC presenter and former England captain Gary Lineker tweeted: "Thoughts are with Rio Ferdinand and his family. How dreadfully sad."
In a statement, the west London club said: "The thoughts of everyone at Queens Park Rangers Football Club are with Rio and his family at this immensely difficult time."
Manchester United said: "Everybody's thoughts at #mufc are with Rio Ferdinand today, whose wife sadly passed away last night."
Ferdinand, who grew up in Peckham, south-east London, was capped by England 81 times and has also played for West Ham United and Leeds United.
Both sets of players wore black armbands in QPR's match against Liverpool at Anfield, which the home team won 2-1.
When Leroy Fer scored in the 73rd minute, he lifted his shirt to reveal a "stay strong family Ferdinand" message.
Other team-mates also tweeted their condolences.
QPR captain Joey Barton posted: "Just heard the terrible news. RIP Rebecca."
Goalkeeper Alex McCarthy wrote: "Devastating news about Rebecca Ferdinand... My thoughts go out to him and his family."
The wife of former Manchester United and England captain Rio Ferdinand has died from cancer.