Defoe dated Joanne Beckham, sister of David Beckham, in the early 2000s.

Defoe's half-brother, Jade Defoe, died of head injuries following an assault in Leytonstone, London, on April 24, 2009.

Defoe's father, Jimmy Defoe, died after a long battle with throat cancer on June 7, 2012.

Defoe befriended Bradley Lowery, a terminally-ill six-year-old fan with neuroblastoma, while playing for Sunderland AFC. Lowery died on July 7, 2017.