The ex-children's television host announced that his spouse Gemma passed away on Saturday evening, three days after falling ill with acute myeloid leukaemia.
Writing on Twitter, the 44-year-old said he was "crushed with indescribable pain" and asked that people who pray remember his eight-year-old son Ethan, who is "in bits".
BBC Breakfast presenter and Christian, Dan Walker offer his support, responding: "There are no words. So sorry to hear my friend. Hold him close".
Simon and Gemma - who was 40 - married in 2005, the same year Simon Thomas joined Sky Sports following his six year spell as a Blue Peter presenter.
A Sky Sports spokesman said: "We are shocked and devastated to hear Simon's news.
"The thoughts of everyone at Sky Sports are with him and his family during this terribly sad time."
Channel 4's Countdown presenter Rachel Riley tweeted Mr Thomas with her "deepest, deepest sympathies", while England football captain Steph Houghton MBE said she was sending "all my love to you and Ethan".
Around 3,100 people in the UK are diagnosed every year with acute myeloid leukaemia, a blood cancer which can affect both children and adults.