"We have decided to part ways and file for divorce," Reham Khan said in a brief statement on her Twitter account Friday.
Imran Khan tweeted that it was a "painful time" and that he has "the greatest respect for Reham's moral character & her passion to work for & help the underprivileged".
Naeem ul Haque, Imran Khan's spokesman, told AFP the decision to divorce was mutual. "It's a painful and personal matter, so I won't be able to comment more or state any reason for it," he said.
Loved by millions across the cricket-obsessed nation for winning Pakistan its only World Cup in 1992, Khan's sporting prowess and rugged good looks also brought him international celebrity in a country lacking glamour.
He was considered his country's most eligible man until he suddenly announced his plans to marry shortly after launching a movement to topple the government in August 2014, which he called off in December after a Taliban attack on a school that killed 150 people.
Reham Khan, host of a local TV talk show, was widely criticised after she appeared at public meetings of Imran Khan's Pakistan Tehreek-i-Insaf (PTI), with opponents accusing her of seeking to boost her own profile through her husband's fame.
She found particularly harsh reception in Khyber Pakhtunkhwa, governed by PTI. She also sparked controversy after it emerged that she had not actually attended a college where she claimed to be a student on her website. There had been reports Imran Khan's family was unhappy with his choice of bride. Imran Khan is the father of two sons from his previous marriage to British socialite Jemima Khan (nee Goldsmith).
Born in 1952 in Lahore into a comfortable family with origins in the Pashtun north-west, he was educated at Aitchison College, the Eton of Pakistan, boarding school in England, and then Oxford University.
He became one of the world's greatest ever all-rounders - a fearsome fast bowler and dangerous batsman - whose finest hour came at the 1992 World Cup, where at the age of 39 he led an inexperienced team to the title.
Off the pitch, he had a string of socialite girlfriends and frequented exclusive nightclubs in London until he married Jemima Goldsmith, the daughter of the French-British tycoon James, in 1995.
She converted to Islam and the couple moved in with his family in Lahore.
They divorced in 2004, allegedly over the difficulties Jemima faced in Pakistan, where she was hounded for her family's Jewish ancestry, and his obsession with politics.-AFP
BR staff reporter Zulfiqar Ahmad adds: Reham Khan's previous marriage with Ijaz Rehman ended after 15 years as the couple divorced in 2005.
The sources within PTI said that Imran was not happy with Reham's growing political ambitions. The sisters of Imran had also been opposing the marriage from the day-one, which the sources said, is also one of the reasons for the split.
The PTI chairman also rejected the rumours that Imran agreed to file a divorce after getting Rs120 million, saying, "Reports and speculation about financial settlements are absolutely false and shameful".
A senior PTI leader who wished not be named said that the couple simply could not get along, adding Imran tried his level best not to go for another divorce but he was left with no option after he realised it is no more possible to live together for him and Reham.
She said that Imran did not want her to get involved in politics but she just could not sit at home like an ordinary housewife. "Imran wanted to persuade her [Reham] that she must not take part in politics, but she wanted to be as prominent as Imran which brought things to this level, as a 'no' from Imran Khan means 'no'", she added.
The PTI chairman never allowed Reham to stay at his Bani Gala residence whenever his sons - Qasim and Suleman - who are staying with their mother Jemima Goldsmith in the UK, visited Pakistan to spend vacations.
The sources said that Imran Khan was also under pressure from his sons, as they also wanted him to end the relationship with Rehman Khan. They said the sisters of Imran Khan especially his elder sister, Aleema, played a role in successfully persuading her nephews - Suleman and Qasim - that their father's marriage was a result of a bad decision by him.