The former Harrods owner is stepping down at Craven Cottage after guiding the club from the third-tier of English football to become a top-flight regular in 16 years at the club.
The West London club were promoted to the Premier League in 2001 and have remained among the elite teams in England since then.
Roy Hodgson's team then beat Hamburg in the semifinals, with the German club anticipating a final in their home stadium.
Now, though, Al-Fayed has sold the club to Khan, who has been the owner of the NFL's Jacksonville Jaguars since November 2011, as the New York Times reported.
Khan, who moved to the United States from Pakistan at the age of 16, is worth £2.9 billion from his automobile parts manufacturing company Flex-N-Gate, according to Forbes.com.
That deal and Khan's acquisition has led to reports that the Jaguars owner could set up a United Kingdom-based NFL franchise.
However, the new Fulham owner batted away those suggestions, as he was unveiled at Craven Cottage alongside Al-Fayed on Saturday in an interview with Sky Sports News.
These are two distinct clubs that will operate differently, operate independently, yet there is a huge amount of synergy, and our goal will be to take advantage of that.
When asked by Sky Sports News reporter Bryan Swanson if Khan ultimately wanted to have the first UK-based NFL franchise, the new Fulham owner said:
Right now, we are committed to playing a game here every year for four years.
Khan has also vowed to support Fulham manager Martin Jol in a bid to make the club successful on the pitch, although he would not reveal what kind of money would be available for squad strengthening this summer.
It's very difficult to be specific. I'm not a micro-manager.
I don't plan on being involved day to day, but I do plan on giving them all the support they need financially, or otherwise, to be successful on the pitch.
While Al-Fayed's time at Craven Cottage has been successful on the field, one issue has riled the Fulham supporters particularly.
Almost two years after singer Michael Jackson died in June 2009, Al-Fayed unveiled a statue of the pop legend in a corner of the Craven Cottage ground, as Philip Duncan of the Daily Mail reported.
However, the Jackson tribute was met with derision by a number of Fulham supporters, as Barney Ronay of The Guardian reported.
Khan has promised to respect the view of supporters, as he considers the future of the statue of Jackson, who was a friend of Al-Fayed but had no links with the club.
I've been an owner less than a day. I think we have to preserve and respect history, but we also have to move forward.
I am going to reflect on it, listen to the fans and then really decide.
Khan is now facing the prospect of continuing the work done by Al-Fayed at Fulham. The Egyptian businessman has overseen a meteoric rise for one of football's historic clubs from the football doldrums to a sustained presence in the Premier League.
The billionaire will need all his business acumen to maintain those standards and progress the London club throughout the coming years.